Compounds useful as pesticides

ABSTRACT

Compounds useful to control pests are provided.

PRIORITY

This application claims priority from U.S. provisional application60/435,928 which was filed on Dec. 20, 2002.

FIELD OF THE INVENTION

This invention provides compounds that are useful as pesticides.

BACKGROUND OF THE INVENTION

There is an acute need for new pesticides. For example, insects andmites are developing resistance to the insecticides and acaricides incurrent use. At least 400 species of arthropods are resistant to one ormore insecticides. The development of resistance to some of the olderinsecticides, such as DDT, the carbamates, and the organophosphates, iswell known. But resistance has even developed to some of the newerpyrethroid insecticides and acaricides. Therefore, a need exists for newinsecticides and acaricides, and particularly for compounds that havenew or atypical modes of action.

DETAILED DESCRIPTION OF THE INVENTION

In Figure One Q, X, Z, R¹, R², R³, and R⁴ have the following meanings.

Q can be any five- or six membered carbocyclic or heterocyclic ring,such as, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl,pyrazolyl, imidazolyl, thienyl, furanyl, thiazolyl, isothiazolyl,oxazolyl, and isoxazolyl, and including reduced forms of theheterocyclic rings such as tetrahydrofuranyl.

X is N, CR, COR, CSO_(n)R (where n=0, 1, or 2), CN(R)₂, C(C═O)R,C(C═S)R, C(C═NR)R, CP(═O)_(m)(R)₂ (where m=0 or 1), or CP(═S)_(m)(R)₂(where m=0 or 1), where each R independently can be

-   -   (a) a C₁₋₁₀, branched or unbranched, alkyl, alkoxy, alkenyl,        alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl,        alkylcarbonothioyl, alkoxycarbonyl, alkylthiocarbonyl,        alkoxycarbonothioyl, alkylthiocarbonothioyl, or HC(═NH)—;    -   (b) a C₃₋₁₀, cycloalkyl, or cycloalkenyl;    -   (c) an aryl, heterocyclyl, aryloxy, heterocyclyloxy, arylthio,        heterocyclylthio, arylamino, or heterocyclylamino; or    -   (d) a hydro, hydroxy, mercapto, amino, cyano, formyl, nitro,        halo, or aminocarbonyl.

Z is CN or NO₂.

R¹ and R² each independently can be:

-   -   (a) a C₁₋₁₀, branched or unbranched, alkyl, alkoxy, alkenyl,        alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl,        alkylcarbonothioyl, alkoxycarbonyl, alkylthiocarbonyl,        alkoxycarbonothioyl, alkylthiocarbonothioyl, or HC(═NH)—;    -   (b) a C₃₋₁₀, cycloalkyl, or cycloalkenyl;    -   (c) an aryl, heterocyclyl, aryloxy, heterocyclyloxy, arylthio,        heterocyclylthio, arylamino, or heterocyclylamino; or    -   (d) a hydro, hydroxy, mercapto, amino, cyano, formyl, nitro,        halo, or aminocarbonyl.

R¹ and R² can optionally be linked together with either a bond or achain of 1-4 atoms, where such atoms can be carbon, nitrogen, sulfur,phosphorus and oxygen.

R³ and R⁴ each independently can be:

-   -   (a) a C₁₋₁₀, branched or unbranched, alkyl, alkoxy, alkenyl,        alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl,        alkylcarbonothioyl, alkoxycarbonyl, alkylthiocarbonyl,        alkoxycarbonothioyl, alkylthiocarbonothioyl, or HC(═NH)—;    -   (b) a C₃₋₁₀, cycloalkyl, or cycloalkenyl;    -   (c) an aryl, heterocyclyl, aryloxy, heterocyclyloxy, arylthio,        heterocyclylthio, arylamino, or heterocyclylamino; or    -   (d) a hydro, hydroxy, mercapto, amino, cyano, formyl, nitro,        halo, or aminocarbonyl.

R² and R³ can optionally be linked together with a chain of 1-4 atoms,where such atoms can be carbon, nitrogen, sulfur, phosphorus and oxygen.

R³ and R⁴ can optionally be linked together with a chain of 1-4 atoms,where such atoms can be carbon, nitrogen, sulfur, phosphorus and oxygen.

Each member of Q, X, R, R¹, R², R³, and R⁴, which may have a hydrogenatom in a certain position, may instead of having such hydrogen atom,have a:

-   -   (a) a C₁₋₁₀, branched or unbranched, alkyl, alkoxy, alkenyl,        alkynyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl,        alkylcarbonothioyl, alkoxycarbonyl, alkylthiocarbonyl,        alkoxycarbonothioyl, alkylthiocarbonothioyl, HC(═NH)—,        dialkylphosphonyl, or dialkylphosphatyl;    -   (b) a C₃₋₁₀, cycloalkyl, or cycloalkenyl;    -   (c) an aryl, heterocyclyl, aryloxy, heterocyclyloxy, arylthio,        heterocyclylthio, arylamino, or heterocyclylamino; or    -   (d) a hydro, hydroxy, mercapto, amino, cyano, formyl, nitro,        halo, or aminocarbonyl;        in such position, provided that these substituents are        sterically compatible and the rules of chemical bonding and        strain energy are satisfied. Figure One is a generic structure.        It should be noted that this generic structure can represent,        depending on the substituents used, two generic isomers due to        the presence of the double bond. These two generic isomers can        exist in a dynamic equilibrium with each other and so        interconvert through tautomeric or canonical forms by free        rotation around the relevant bond. This invention comprises all        such interconverting isomers and purified derivatives thereof.        The nature of tautomeric and canonical forms is understood to be        as described in “Advanced Organic Chemistry: Reactions,        Mechanisms and Structure”, 4^(th) edition, J. March ed., John        Wiley and Sons, New York, 1992.

The term “aryl” means a monovalent radical derived by loss of hydrogenfrom an aromatic hydrocarbon. The term heterocyclyl means a monovalentradical derived by loss of a hydrogen from an ring structure, where suchring structure contains one or more nitrogen, oxygen, or sulfur atoms.Examples of aryls and heterocyclyl include, but are not limited to,phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrrolyl, pyrazolyl, imidazolyl, thienyl, furanyl, thiazolyl,isothiazolyl, oxazolyl, and isoxazolyl, and included are reduced formsof the heterocyclyl such as tetrahydrofuranyl.

All salts and esters of these compounds are contemplated as part of thisinvention.

The compounds of the invention are useful for the control pests such as,insects and mites. Therefore, the present invention also is directed toa method for inhibiting an insect or mite, which comprises applying to alocus of the insect or mite an insect- or mite-inhibiting amount of acompound of this invention in particular, these compounds controlinsects in the order Homoptera, including the families Aphididae(aphids), Aleyrodidae (whiteflies), Delphacidae (planthoppers), andCicadellidae (leafhoppers). They also control insects in the orderColeoptera (beetles), including the family Chrysomelidae (leaf beetles),as well as Lepidopteran insects such as caterpillars. In particular,other representative pests which may be controlled by the method of thisinvention include members of the Arthropoda, including mites of thesuborders Mesostigmata, Sarcoptiformes, Trombidiformes andOnchychopalpida; sucking and biting lice of the orders Anoplura andMallophaga: ticks of the families Ixodidae and Argasidae: fleas of thefamilies Pulicidae, Ceratophyllidae, and others; Cimex and otherHemiptera; Triatoma and other Heteroptera: and myiasis-related flylarvae and blood sucking adults (including mosquitoes) of the subordersBrachycera, Cyclorrhapha and Nematocera. Representative also arehelminths included in the Nematoda (Strongylida, including but notlimited to Strongyloidea, Ancylostomatoidea, Trichostrongyloidea andMetastrongyloidea; Ascarida Ascarisi; Filarina, such as but not limitedto Onchocerca and Dirofilaria; Rhabditida; and Trichinellida);Cestoidea, especially Cyclophyllidea, and Trematoda, includingStrigeatoidea such as Schistosoma; Echinostomida such as Fasciola: andPlagiorchilda such as Paraqonimus. Other pests which may be controlledby compounds of this invention Acanthocephala such asMacracanthorhynchus, Onicola or Moniliformis, and Pentastomida,especially Linguatula; and Protozoa, especially Coccidia such as Eimeriaand Plasmodium, Piroplasmea such as Babesia; Toxoplasmea such asTrypanosoma; Trichomonadidae such as Trichomonas and Entamoebidae suchas Entamoeba. Illustrative of specific pests of various animals whichmay be controlled by the method of this invention include arthropodssuch as mites (mesostigmatids, itch. mange, scabies. chiggers), ticks(soft-bodied and hard-bodied), lice (sucking, biting), fleas (dog flea,cat flea, oriental rat flea), true bugs (bed bugs, kissing bugs),bloodsucking adult flies (horn fly, horse fly, stable fly. black fly.deer fly, louse fly, tsetse fly, punkies, mosquitoes). and parasitic flymaggots (bot fly, blow fly, screwworm, cattle grub, fleeceworm);helminths such as nematodes (threadworm, lungworm, hookworm, whipworm,nodular worm. stomach worm, round worm, pinworm, heartworm), cestodes(tapeworms) and trematodes (liver fluke, blood fluke); protozoa such ascoccidia, trypanosomes, trichomonads, amoebas and plasmodia;acanthocephalans such as thorny-headed worms; and pentastomids such astongueworms.

The compounds are useful for reducing populations of insects and mitesand are useful in a method of inhibiting an Insect or mite populationwhich comprises applying to a locus of the insect or mite an effectiveinsect- or mite-inactivating amount of a compound of this invention.

The “locus” of insects or mites is a term used herein to refer to theenvironment in which the insects or mites live or where their eggs arepresent, including the air surrounding them, the food they eat, orobjects or materials which they contact. For example, plant-ingestinginsects or mites can be controlled by applying the active compound toplant parts that the insects or mites eat, particularly the foliage.Soil-inhabiting insects such as termites can be controlled by applyingthe active compound to the soil that the insects move through. Insectssuch as fleas that infest animals can be controlled by applying theactive compound to the animal that is infested. Oral administration ofthe compounds of this invention may be performed by mixing the compoundin the animal's feed or drinking water, vitamin or mineral supplement,or by administering oral dosage forms such as drenches, tablets, bolus,salt block or capsules.

It is contemplated that the compounds might also be useful to protecttextiles, paper, stored grain, or seeds by applying an active compoundto such substance.

The term “inhibiting an insect or mite” refers to a decrease in thenumbers of living insects or mites, or a decrease in the number ofviable insect or mite eggs. The extent of reduction accomplished by acompound depends, of course, upon the application rate of the compound,the particular compound used, and the target insect or mite species. Atleast an inactivating amount should be used.

The terms “insect-inactivating amount” and “mite-inactivating amount”are used to describe the amount, which is sufficient to cause ameasurable reduction in the treated insect or mite, population.Generally an amount in the range from about 1 to about 1000 ppm byweight active compound is used. In another embodiment, the presentinvention is directed to a method for inhibiting a insect or mite, whichcomprises applying to a plant an effective insect or mite inactivatingamount of a compound of this invention.

The compounds of this invention are applied in the form of compositionswhich comprise a compound of this invention and aphytologically-acceptable inert carrier. The compositions are eitherconcentrated formulations which are dispersed in water for application,or are dust or granular formulations which are applied without furthertreatment. The compositions are prepared according to procedures andformulae which are conventional in the agricultural chemical art, butwhich are novel and important because of the presence therein of thecompounds of this invention.

The dispersions in which the compounds are applied are most oftenaqueous suspensions or emulsions prepared from concentrated formulationsof the compounds. Such water-soluble, water-suspendable or emulsifiableformulations are either solids, usually known as wettable powders, orliquids usually known as emulsifiable concentrates or aqueoussuspensions. Wettable powders, which may be compacted to form waterdispersible granules, comprise an intimate mixture of the activecompound, an inert carrier, and surfactants. The concentration of theactive compound is usually from about 10% to about 90% by weight. Theinert carrier is usually chosen from among the attapulgite clays, themontmorillonite clays, the diatomaceous earths, or the purifiedsilicates.

Effective surfactants, comprising from about 0.5% to about 10% of thewettable powder, are found among the sulfonated lignins, the condensednaphthalenesulfonates, the naphthalenesulfonates, thealkylbenzene-sulfonates, the alkyl sulfates, and nonionic surfactantssuch as ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of the compounds comprise a convenientconcentration of a compound, such as from about 50 to about 500 gramsper liter of liquid, equivalent to about 10% to about 50%, dissolved inan inert carrier which is either a water miscible solvent or a mixtureof water-immiscible organic solvent and emulsifiers. Useful organicsolvents include aromatics, especially the xylenes, and the petroleumfractions, especially the high-boiling naphthalenic and olefinicportions of petroleum such as heavy aromatic naphtha. Other organicsolvents may also be used, such as the terpenic solvents including rosinderivatives, aliphatic ketones such as cyclohexanone, and complexalcohols such as 2-ethoxyethanol. Suitable emulsifiers for emulsifiableconcentrates are chosen from conventional nonionic surfactants, such asthose discussed above.

Aqueous suspensions comprise suspensions of water-insoluble compounds ofthis invention, dispersed in an aqueous vehicle at a concentration inthe range from about 5% to about 50% by weight. Suspensions are preparedby finely grinding the compound, and vigorously mixing it into a vehiclecomprised of water and surfactants chosen from the same types discussedabove. Inert ingredients, such as inorganic salts and synthetic ornatural gums, may also be added, to increase the density and viscosityof the aqueous vehicle. It is often most effective to grind and mix thecompound at the same time by preparing the aqueous mixture, andhomogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer.

The compounds may also be applied as granular compositions, which areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% by weight of the compound,dispersed in an inert carrier which consists entirely or in large partof clay or a similar inexpensive substance. Such compositions areusually prepared by dissolving the compound in a suitable solvent andapplying it to a granular carrier which has been pre-formed to theappropriate particle size, in the range of from about 0.5 to 3 mm. Suchcompositions may also be formulated by making a dough or paste of thecarrier and compound and crushing and drying to obtain the desiredgranular particle size.

Dusts containing the compounds are prepared simply by intimately mixingthe compound in powdered form with a suitable dusty agriculturalcarrier, such as kaolin clay, ground volcanic rock, and the like. Dustscan suitably contain from about 1% to about 10% of the compound.

The active compositions may contain adjuvant surfactants to enhancedeposition, wetting and penetration of the compositions onto the targetcrop and organism. These adjuvant surfactants may optionally be employedas a component of the formulation or as a tank mix. The amount ofadjuvant surfactant will vary from 0.01 percent to 1.0 percent v/v basedon a spray-volume of water, preferably 0.05 to 0.5 percent. Suitableadjuvant surfactants include ethoxylated nonyl phenols, ethoxylatedsynthetic or natural alcohols, salts of the esters of sulphosuccinicacids, ethoxylated organosilicones, ethoxylated fatty amines, crop oilconcentrates containing high molecular weight paraffinic oils and blendsof surfactants with mineral and vegetable oils.

It is equally practical, when desirable for any reason, to apply thecompound in the form of a solution in an appropriate organic solvent,usually a bland petroleum oil, such as the spray oils, which are widelyused in agricultural chemistry.

Insecticides and acaricides are generally applied in the form of adispersion of the active ingredient in a liquid carrier. It isconventional to refer to application rates in terms of the concentrationof active ingredient in the carrier. The most widely used carrier iswater.

The compounds of the invention can also be applied in the form of anaerosol composition. In such compositions the active compound isdissolved or dispersed in an inert carrier, which is apressure-generating propellant mixture. The aerosol composition ispackaged in a container from which the mixture is dispensed through anatomizing valve. Propellant mixtures comprise either low-boilinghalocarbons, which may be mixed with organic solvents, or aqueoussuspensions pressurized with inert gases or gaseous hydrocarbons.

The actual amount of compound to be applied to loci of insects and mitesis not critical and can readily be determined by those skilled in theart in view of the examples above. In general, concentrations of from-10ppm to 5000 ppm by weight of compound are expected to provide goodcontrol. With many of the compounds, concentrations of from 100 to 1500ppm will suffice.

The locus to which a compound is applied can be any locus inhabited byan insect or arachnid, for example, vegetable crops, fruit and nuttrees, grape vines, and ornamental plants.

Because of the unique ability of mite eggs to resist toxicant action,repeated applications may be desirable to control newly emerged larvae,as is true of other known acaricides.

In addition to being effective against mites and insects when applied tofoliage, compounds of this invention have systemic activity.Accordingly, another aspect of the invention is a method of protecting aplant from insects or mites which comprises treating plant seed prior toplanting it, treating soil where plant seed is to be planted, ortreating soil at the roots of a plant after it is planted, with aneffective amount of a compound of this invention.

The action of the inventive compounds can be broadened by adding other,for example insecticidally, acaricidally, and/or nematocidally active,ingredients. For example, one or more of the following compounds cansuitably be combined with the compounds of the invention:

-   -   (1) organophosphorus compounds such as acephate, azinphosmethyl,        cadusafos, chlorethoxyfos, chlorpyrifos, coumaphos, dematon,        demeton-5-methyl, diazinon, dichlorvos, dimethoate, EPN,        erthoate, ethoprophos, etrimfos, fenamiphos, fenitrothion,        fensulfothion, fenthion, fonofos, formothion, fosthiazate,        heptenophos, malathion, methamidophos, methyl parathion,        mevinphos, monocrotophos, parathion, phorate, phosalone,        phosmet, phosphamidon, phosphocarb, phoxim, profenofos,        propaphos, propetamphos, prothiofos, pyrimiphos-methyl,        pyrimiphos-ethyl, quinalphos, sulprofos; tebupirimphos,        temephos, terbufos, tetrachlorvinphos, thiafenox, thiometon,        triazophos, and trichlorphon;    -   (2) carbamates such as aldicarb, bendiocarb, benfuracarb,        bensultap, BPMC, butoxycarbocim, carbaryl, carbofuran,        carbosulfan, cloethocarb, ethiofencarb, fenobucarb,        furathiocarb, methiocarb, isoprocarb, methomyl, oxamyl,        pirimicarb, promecarb, propoxur, thiodicarb, and thiofurox;    -   (3) pyrethroids such as acrinathrin, allethrin, beta-cyfluthrin,        bifenthrin, bioresmethrin, cyfluthrin; cyhalothrin;        lambda-cyhalothrin; gamma-cyhalothrin, cypermethrin;        alpha-cypermethrin; zeta-cypermethrin; deltamethrin,        esfenvalerate, fenvalerate, fenfluthrin, fenpropathrin,        flucythrinate, flumethrin, fluvalinate, tau-fluvalinate,        halfenprox, permethrin, protrifenbute, resmethrin, silafluofen,        tefluthrin, tetramethrin, tralomethrin, fish safe pyrethroids        for example ethofenprox, natural pyrethrin, tetramethrin,        s-bioallethrin, fenfluthrin and prallethrin;    -   (4) acylureas, other types of insect growth regulators and        insect hormone analogs such as buprofezin, chromfenozide,        chlorfluazuron, diflubenzuron, fenoxycarb, flufenoxuron,        halofenozide, hexaflumuron, hydroprene, leufenuron, methoprene,        methoxyfenozide, novaluron, pyriproxyfen, teflubenzuron and        tebufenozide,        N-[3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-N′(2,6-difluorobenzoyl)urea;    -   (5) neonicotnioids and other nicotinics such as acetamiprid,        AKD-1022, cartap, TI-435, clothianidin, MTI-446, dinotefuran,        imidacloprid, nicotine, nitenpyram, thiamethoxam, thiacloprid;    -   (6) macrolides such as avermectins, milbemycins, or spinosyns        for example such as abamectin, ivermectin, milbemycin, emamectin        benzoate and spinosad; and    -   (7) other insecticidal, acaricidal, mollscicial and nematocidal        compounds or actives such as aldrin, amitraz, azadirachtin,        azocyclotin. bifenazate, bromopropylate, chlordimeform,        chlorfenapyr, clofentezine, chlorobenzilate, chlordane,        cyhexatin, cyromazin, DDT, dicofol, dieldrin, DNOC, endosulfan,        ethoxazole, fenazaquin, fenbutatin oxide, fenproximate,        beta-fenpyroximate, fipronil, flubenzimine, hexythiazox,        IKI-220, indoxacarb, lindane, methiocarb, metaldehyde,        methoxychlor, neem, petroleum and vegetable oils, pyridaben,        pymetrozine, pyrimidifen, rotenone, S-1812, S-9539,        spirodiclofen, sulfur, tebufenpyrad, tetradifon, triazamate, an        insect-active extract from a plant; a preparation containing        insect-active nematodes, a preparation obtainable from Bacillus        subtilis, Bacillus thuringiensis, a nuclear polyhedrosis virus,        or other like organism genetically modified or native, as well        as synergists such as piperonyl butoxide, sesamax, safroxan and        dodecyl imidazole, and phagostimulants such as cucurbitacin,        sugars and Coax.

EXAMPLES

These examples are provided to further illustrate the invention.

Example A Preparation of Preparatory Compound A

A 2.1 g (12 mmol) portion of Preparatory Compound F dissolved in 70 mLof a 10:1 mixture of ethyl acetate and methanol was carefully treatedwith 7.0 mL of a 2.0 M solution of trimethylsilyldiazomethane dissolvedin hexanes. After vigorous gas formation had subsided, the solvent wasremoved under reduced pressure to yield 2.5 g (quantitative) ofPreparatory Compound A, methyl (6-chloro-3-pyridinyl)acetate, as a brownoil: GCMS: (EI) m/z 185 (M+).

Example B Preparation of Preparatory Compound B

A solution of 1.45 g (7.84 mmol) of Preparatory Compound A in 10 mL of40% aqueous methylamine in acetonitrile was stirred vigorously at roomtemperature (about 22° C.) and monitored by reverse-phase chromatographyuntil the reaction was complete. The solvents were removed under reducedpressure and the solid residue dried in a vacuum oven at 50° C.overnight to give 1.39 g (96%) of Preparatory Compound B,2-(6-chloro-3-pyridinyl)-N-methylacetamide, as a light brown solid: ¹HNMR (CDCl₃) δ 8.30 (d, J=3.0 Hz, 1H), 7.68 (dd, J=3.0 and 8.0 Hz, 1H),7.34 (d, J=8.0 Hz, 1H), 5.50 (bs, 1H), 3.54 (s, 2H), 2.83 (d, J=4.8 Hz,3H) ppm. GCMS: (EI) m/z 184 (M+).

Example C Preparation of Preparatory Compound C

A solution of 714 mg (3.88 mmol) of Preparatory Compound B in 10 mL ofpyridine was treated with 0.44 g (0.99 mmol) of phosphorus pentasulfideand heated at 80° C. for 18 hours. The dark mixture was partitionedbetween dichloromethane and 1M hydrochloric acid and the organic layerdried over sodium sulfate. A portion of silica gel was added and thesolvent was removed under reduced pressure. The residue impregnatedsilica gel was then placed on top of a column of silica gel and elutedwith 30-50% ethyl acetate in petroleum ether. The solvent was againremoved under reduced pressure to leave 580 mg (75%) of PreparatoryCompound C, 2-(6-chloro-3-pyridinyl)-N-methylethanethioamide, as a lightyellow solid: mp 140-141° C.; ¹H NMR (CDCl₃) δ 8.25 (d, J=3.0 Hz, 1H),7.72 (dd, J=3.0 and 8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 4.02 (s, 2H),3.18 (s, 3H) ppm. GCMS: (EI) m/z 200 (M+). Anal. Calcd for C₈H₉ClN₂S: C,47.9; H, 4.52; N, 14.0. Found: C, 48.3; H, 4.51; N, 13.4.

Example D Preparation of Preparatory Compound D

A solution of 370 mg (1.85 mmol) of Preparatory Compound C in 5 mL ofdry dimethylformamide was treated with 85 mg (2.1 mmol) of 60% sodiumhydride in oil under nitrogen at room temperature (about 22° C.). Aftergas evolution had subsided, the green solution was treated with 0.2 mL(3.2 mmol) of iodomethane. The mixture was partitioned between water andether and the organic layer was dried over sodium sulfate. The solventwas removed under reduced pressure and the residue dried further byazeotropic removal of water with dichloromethane to yield PreparatoryCompound D, methyl-2-(6-chloropyridin-3-yl)-N-methylpropanimidothioate,as a mixture in mineral oil: GCMS: (EI) m/z 214 (M+).

Example E Preparation of Preparatory Compound E

A solution of 5.2 g (32 mmol) of 2-chloro-5-chloromethylpyridinedissolved in 40 mL of ethanol was treated with 20 mL of water and 2.4 g(37 mmol) of potassium cyanide. The mixture was stirred and heated at50° C. for 20 hours. The dark mixture was then partitioned betweendichloromethane and water and the organic layer was washed with brineand dried over sodium sulfate. The solvent was removed under reducedpressure to yield 4.54 g (92%) of Preparatory Compound E,(6-chloro-3-pyridinyl)acetonitrile, as a dark brown liquid: ¹H NMR(CDCl₃) δ 8.38 (d, J=3.0 Hz, 1H), 7.71 (dd, J=3.0 and 7.6 Hz, 1H), 7.42(d, J=7.6 Hz, 1H), 3.80 (s, 2H) ppm. GCMS: (EI) m/z 152 (M+).

Example F Preparation of Preparatory Compound F

A 4.45 g (29.3 mmol) portion of Preparatory Compound E was treated with5 mL of concentrated hydrochloric acid. The mixture was stirred andheated at 80° C. for 24 hours. The solution was poured in to ice and theresulting precipitate filtered. Residual water was removed from thesample by treatment with toluene and removal of the azeotrope underreduced pressure. This procedure yielded 3.93 g (78%) of PreparatoryCompound F, (6-chloro-3-pyridinyl)acetic acid, as a fine yellow powder:mp 170-171° C.; ¹H NMR (CDCl₃) δ 8.34 (di J=3.0 Hz, 1H), 7.66 (dd, J=3.0and 8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 3.70 (s, 2H) ppm. MS: (ES+) m/z172 (M+). Anal. Calcd for C₇H₆ClNO₂: C, 49.0; H, 3.52; N, 8.16. Found:C, 49.3; H, 3.53; N, 8.11.

Example G Preparation of Preparatory Compound G

A dry flask was charged with anhydrous tetrahydrofuran (20 mL) andcooled to −78° C. Preparatory Compound A (0.5 g, 0.0027 mol) was added,followed by dropwise addition of butyllithium (2.5 M in tetrahydrofuran,1.2 mL, 0.0029 mol). The resulting mixture was stirred at −78° C. for 10minutes, then iodomethane (3.45 g, 0.0243 mol) was added dropwise withstirring. The mixture was allowed to slowly warm to room temperature(about 22° C.) and stirred at room temperature for 18 hours. Theresulting solution was dissolved in dichloromethane, washed withsaturated aqueous ammonium chloride, and dried over magnesium sulfate.The solution was concentrated to yield 0.54 g of crude PreparatoryCompound G, methyl 2-(6-chloro-3-pyridinyl)propanoate, as a dark yellowliquid (90% purity).

Example H Preparation of Preparatory Compound H

A solution of 1.50 g (7.51 mmol) of Preparatory Compound G in 10 mL of40% aqueous methylamine was stirred vigorously at room temperature(about 22° C.) and monitored by reverse-phase chromatography until thereaction was complete. The solvents were removed under reduced pressureand the solid residue dried in a vacuum oven at 50° C. overnight to give1.48 g (quantitative) of Preparatory Compound H,2-(6-chloro-3-pyridinyl)-N-methylpropanamide, as a white solid: mp91-93° C.; ¹H NMR (CDCl₃) δ 8.28 (d, J=3.0 Hz, 1H), 7.74 (dd, J=3.0 and8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 3.50 (q, J=6.4 Hz, 1H), 2.78 (d,J=4.8 Hz, 3H), 1.52 (d, J=6.4 Hz, 3H) ppm. GCMS: (EI) m/z 198 (M+).Anal. Calcd for C₉H₁₁ClN₂O: C, 54.4; H, 5.58; N, 14.1. Found: C, 54.1;H, 5.60; N, 13.8.

Example I Preparation of Preparatory Compound I

A solution of 1.48 g (7.47 mmol) of Preparatory Compound H in 20 mL ofpyridine was treated with 0.87 g (1.96 mmol) of phosphorus pentasulfideand heated at 80° C. for 18 hours. The dark mixture was partitionedbetween dichloromethane and 1M hydrochloric acid and the organic layerdried over sodium sulfate. A portion of silica gel was added and thesolvent was removed under reduced pressure. The residue impregnatedsilica gel was then placed on top of a column of silica gel and elutedwith 30-50% ethyl acetate in petroleum ether. The solvent was againremoved under reduced pressure to leave 1.27 g (79%) of PreparatoryCompound I, 2-(6-chloro-3-pyridinyl)-N-methylpropanethioamide, as alight yellow solid: mp 130-131° C.; ¹H NMR (CDCl₃) δ 8.26 (d, J=3.0 Hz,1H), 7.88 (dd, J=3.0 and 8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 4.02 (q,J=7.4 Hz, 1H), 3.14 (d, J=5.6 Hz, 3H), 1.66 (d, J=7.4 Hz, 3H) ppm. GCMS:(EI) m/z 214 (M+). Anal. Calcd for C₉H₁₁CIN₂S: C, 50.3; H, 5.16; N,13.0. Found: C, 50.0; H, 5.13; N, 12.6.

Example J Preparation of Preparatory Compound J

A solution of 162 mg (0.76 mmol) of Preparatory Compound I in 5 mL ofdry dimethylformamide was treated with 36 mg (0.90 mmol) of 60% sodiumhydride in oil under nitrogen at room temperature (about 22° C.). Aftergas evolution had subsided, the green solution was treated with 0.25 mL(4.0 mmol) of iodomethane. The mixture was partitioned between water andether and the organic layer was dried over sodium sulfate. The solventwas removed under reduced pressure and the residue dried further byazeotropic removal of water with dichloromethane to yield PreparatoryCompound J, methyl 2-(6-chloro-3-pyridinyl)-N-methylpropanimidothioate,as a mixture in mineral oil: GCMS: (EI) m/z 228 (M+).

Example K Preparation of Preparatory Compound K

To a solution at −5° C. of 44 mL of absolute ethanol in 155 mL ofchloroform under nitrogen was added dropwise 45 mL of acetyl chloride.After 0.5 hours a solution of 8.46 g (55.4 mmol) of Preparatory CompoundE in 71 mL of chloroform was added dropwise keeping the temperature at0° C. or below. The mixture was then kept at 0° C. for 4 hours and wasthen allowed to warm to room temperature overnight (about 22° C.). Ethylether was added (350 mL) with cooling and the mixture was stirred forseveral minutes and was then filtered through a medium porosity sinteredglass funnel always careful to keep a layer of ether over the whitesolid. After washing with an ample amount of ether, the solid/ethermixture was washed into a 1 L three-neck round-bottomed flask fittedwith a mechanical stirrer and was then diluted with 400 mL of ether andwas treated dropwise with 12.34 g (122 mmol, 2.2 equiv.) oftriethylamine in ether while cooling. The contents were stirredovernight under nitrogen. The mixture was filtered, the filtrate wasdried over sodium sulfate and was concentrated to give 9.91 g (90%) ofPreparatory Compound K, ethyl 2-(6-chloro-3-pyridinyl)ethanimidoate, asan oil.

Example L Preparation of Preparatory Compound L

A stirring solution of 3.00 g (17.5 mmol) of Preparatory Compound F indry dimethylformamide was cooled to −78° C. and treated dropwise with21.0 mL of 2.5M n-butyllithium in hexanes under a nitrogen atmosphere.This solution was then treated with 7.0 mL (88 mmol) of ethyl iodide inone portion. The mixture was allowed to warm to room temperature (about22° C.) and then partitioned between dichloromethane and 1M hydrochloricacid, dried over sodium sulfate and the solvent removed under reducedpressure. The resulting dark yellow oil was purified by dissolving inaqueous sodium bicarbonate, washing with diethyl ether, and acidifyingwith hydrochloric acid. The resulting cloudy aqueous solution was thenextracted with dichloromethane, dried over sodium sulfate and thesolvent removed under reduced pressure to yield 1.90 g (55% ofPreparatory Compound L, 2-(6-chloro-3-pyridinyl)butanoic acid, as ayellow oil: ¹H NMR (CDCl₃) δ 8.34 (d, J=2.8 Hz, 1H), 7.68 (dd, J=2.8 and8.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 3.50 (t, J=6.9 Hz, 1H), 2.16 (m,1H), 1.82 (m, 1H) 0.96 (t, J=6.9 Hz, 3H) ppm. GCMS: (EI) m/z 199 (M).Anal. Calcd for C₉H₁₀ClNO₂: C, 54.2; H, 5.05; N, 7.02. Found: C, 53.9;H, 4.83; N, 6.93.

Example M Preparation of Preparatory Compound M

A solution of 2.2 g (11 mmol) of Preparatory Compound L in 100 mL ofdichloromethane was treated with 1.5 g (16 mmol) of phenol, 11 mL of a1.0 M solution of dicyclohexylcarbodiimide in dichloromethane and 0.14 g(1.1 mmol) 4-dimethylaminopyridine. The reaction mixture was stirred for3 hours at room temperature (about 22° C.) and then diluted with etherand the precipitate removed by filtration through a bed of Cellite. Theorganic solution was washed with water, dried over sodium sulfate andthe solvent removed under reduced pressure. The resulting residue wasdissolved in acetonitrile and the solids removed by filtration through abed of Cellite. The solvent was removed under reduced pressure to yieldapproximately 3.0 g of Preparatory Compound M, phenyl2-(6-chloro-3-pyridinyl)butanoate, as a yellow oil.

Example N Preparation of Preparatory Compound N

A solution of 3.67 g (32.8 mmol) of potassium t-butoxide in 30 mL of drydimethylsulfoxide was cooled with an ice bath and treated with 1.77 mL(32.8 mmol) of nitromethane dropwise such that the temperature wasmaintained at approximately 20° C. After 45 min, a solution ofPreparatory Compound M in a few mL of dry dimethylsulfoxide was addedand the reaction mixture stirred for 5.5 hours. The reaction mixture wasthen quenched with a few mL of water and 1 g of urea. While cooling withice, the pH was adjusted to approximately 1 using 1M hydrochloric acid.The mixture was then extracted with diethyl ether, the organic layerdried over sodium sulfate and the solvent removed under reducedpressure. The residue was purified by reverse phase preparative HPLCusing a Waters AMQ column and a 50% acetonitrile/water mixture with 0.1%phosphoric acid as the eluent. The isolated fraction was extracted withdichloromethane, the organic layer dried over sodium sulfate and thesolvent removed under reduced pressure to give 1.40 g (53%) ofPreparatory Compound N, 3-(6-chloro-3-pyridinyl)-1-nitro-2-pentanone, asa yellow oil: ¹H NMR (CDCl₃) δ 8.28 (d, J=3.2 Hz, 1H), 7.56 (dd, J=3.2and 8.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 5.24 (dd, J=16 and 28 Hz, 2H),3.68 (dd, J=7.9 and 9.5 Hz, 1H), 2.16 (m, 1H), 1.80 (m, 1H), 0.90 (t,J=7.7 Hz, 3H) ppm. MS: (ES−) m/z 241 (M−1).

Example O Preparation of Preparatory Compound O

A solution of 0.70 g (2.9 mmol) Preparatory Compound N in 5 mL ofethanethiol was treated with 1.94 g (14.3 mmol) of zinc chloride and thethick slurry allowed to stir 18 hours. After 18 hours, the slurry hadturned into a clear orange viscous solution. The reaction mixture wastreated with water and extracted exhaustively with dichloromethane. Theorganic layer was dried over sodium sulfate and the solvent removedunder reduced pressure to give 0.70 g of a yellow syrup that was amixture of products containing Preparatory Compound O,2-chloro-5-[1-ethyl-2,2-bis(ethylthio)-3-nitropropyl]pyridine.

Example P Preparation of Preparatory Compound P

2,3-dichloro-5-trichloromethylpyridine (36.60 g, 0.139 mol) was added toa flask containing acetic acid (53.50 g, 0.892 mol) and methanol (200mL). The mixture was cooled to −5° C., and zinc dust (20.01 g, 0.308mol) was added in small portions at 10 minute intervals. The mixture wasstirred mechanically for 4 hours, filtered, and concentrated in vacuo.The residue was dissolved in dichloromethane and washed with brine,followed by saturated aqueous sodium bicarbonate, followed by a secondbrine wash. The organic phase was dried over magnesium sulfate andconcentrated in vacuo to yield 21.55 g (79%) of Preparatory Compound P,2,3-dichloro-5-(chloromethyl)pyridine, as a yellow liquid (about 65%purity). ¹H NMR δ 8.31 (d, 1H, J=2.3 Hz), 7.85 (q, 1H, J=0.4 Hz andJ=2.2 Hz), 4.56 (s, 2H). MS (ESI) m/z 199 ([M+4]⁺, 8), 197 ([M+2]⁺, 27),195 ([M]⁺, 28), 164 (11), 162 (66), 160 (100), 124 (19)

Example Q Preparation of Preparatory Compound Q

Potassium cyanide (0.47 g, 0.00714 mol) was added to a flask containingPreparatory Compound P in ethanol (25 mL). The mixture was heated atreflux overnight. The mixture was dissolved in dichloromethane andwashed twice with water. The organic phase was dried over magnesiumsulfate and concentrated in vacuo to obtain a reddish oil. The oil waspurified by silica gel chromatography using 50% ethyl acetate/hexanes aseluents. Fractions containing the desired product were isolated andconcentrated in vacuo to yield Preparatory Compound Q,(5,6-dichloropyridin-3-yl)acetonitrile, as a purple solid. (0.450 g,39%). ¹H NMR δ 8.28 (d, 1H, J=2.1 Hz), 7.83 (dd, 1H, J=0.7 Hz and J=1.6Hz), 3.78 (s, 2H). MS (ESI) m/z 190 ([M+4]⁺, 10), 188 ([M+2]⁺, 64), 186([M]⁺, 99), 151 (100), 124 (39).

Example R Preparation of Preparatory Compound R

Acetyl chloride (5.29 g, 0.0674 mol) was added dropwise to a flaskcontaining ethanol (4.8 mL) in chloroform (17 mL) at 0° C. The mixturewas stirred at 0° C. for 15 minutes, then a solution of PreparatoryCompound Q (1.10 g, 0.00591 mol) in chloroform (17.5 mL) was addeddropwise. The mixture was stirred for 5 hours at 0° C., during whichtime a pale precipitate formed, then allowed to slowly warm to roomtemperature (about 22° C.). The mixture was stirred at room temperatureovernight then 40 mL of ethanol was added to the flask, and theoff-white precipitate was collected in a sintered glass funnel andwashed several times with diethyl ether, keeping a thin layer of solventover the material at all times. The solid was washed over into around-bottomed flask with diethyl ether, and triethylamine (0.66 g,0.00650 mol) was added. The mixture was stirred at room temperatureovernight. The resulting mixture was filtered through a sintered glassfunnel. The filtrate was dried over sodium sulfate and concentrated invacuo to yield 0.930 g (68%) of Preparatory Compound R,ethyl-2-(5,6-dichloropyridin-3-yl)ethanimidoate, as a dark orange oil.¹H NMR δ 8.19 (d, 1H, J=2.3 Hz), 7.69 (s, 1H), 4.13 (br s, 2H), 3.54 (s,2H), 1.30 (t, 3H, J=7.1 Hz). MS (ESI) m/z 236 ([M+4]⁺, 2), 234 ([M+2]⁺,11), 232 ([M]⁺, 16), 204 (12), 188 (35), 174 (73), 161 (100), 151 (37),124 (43).

Example S Preparation of Preparatory Compound S

A mixture of 0.500 g (2.69 mmol) of Preparatory Compound A and 479 mg(2.69 mmol) of N-bromosuccinimide in 5 mL of carbon tetrachloride wastreated with 5 mg of azo-bis-isobutyronitrile and was heated at refluxfor four hours and was allowed to cool. The mixture was concentrated todryness and the residue was chromatographed on silica gel (230-400 mesh)using 95/5 dichloromethane/ethyl acetate as eluent to afford 353 mg(50%) of Preparatory Compound S methylbromo(6-chloro-3-pyridinyl)acetate as an oil; ¹HNMR (CDCl₃) δ 8.44 (d,1H, J=2.6 Hz), 7.98 (dd, 1H, J=8.3 Hz and J=2.5 Hz), 7.38 (d, 1H, J=8.5Hz), 5.33 (s, 1H), 3.82 (s, 3H); MS (ES+) m/z 265 ([M+H]⁺).

Example T Preparation of Preparatory Compound T

To a solution at 15-20° C. of 8.4 mL (7.55 g, 0.126 mol) ofethylenediamine in 15 mL of dry tetrahydrofuran was added dropwise overa five minute period a solution of 3.2 g (0.012 mol) of PreparatoryCompound S in 35 mL of tetrahydrofuran. The mixture was stirredmechanically for 18 h and was then treated with 2.0 g of potassiumcarbonate and was stirred for four hours. The contents were filtered,the filtrate was concentrated to dryness, and the solid residue wasdissolved in 400 mL of dichloromethane and was washed with 20 mL of 10%aqueous potassium carbonate and was then dried over potassium carbonate.Concentration gave 2.61 g of a tan solid. A portion (250 mg) waschromatographed on silica gel (230-400 mesh) using 9/1dichloromethane/methanol containing 5% ammonium hydroxide to afford 186mg of Preparatory Compound T 3-(6-chloro-3-pyridinyl)-2-piperazinone asa white solid, mp 157-9° C.; ¹HNMR (CDCl₃) δ 8.50 (d, 1H, J=2.7 Hz),7.90 (dd, 1H, J=8.4 Hz, and J=2.5 Hz), 7.31 (d, 1H, J=8.2 Hz), 6.37 (brs, 1H), 4.59 (s, 1H), 3.53-3.61 (m, 1H), 3.35-3.40 (m, 1H), 3.08-3.18(m, 2H), 2.01 (br s, 1H); MS (EI-DIP) m/z 213 ([M+2]⁺, 7), 211 (M+, 25),154 (100).

Example U Preparation of Preparatory Compound U

To a solution at 10-20° C. of 2.11 g (9.67 mmol) ofdi-t-butyldicarbonate in 35 mL of dry tetrahydrofuran was added inportions over a ten minute period 2.00 g (9.45 mmol) of PreparatoryCompound T. After stirring at room temperature for 18 h thetetrahydrofuran was removed in vacuo at room temperature and the residuewas dissolved in dichloromethane and was washed once with water. Theaqueous wash was treated with saturated sodium bicarbonate and wasextracted once with dichloromethane. The combined organics were driedover magnesium sulfate and were concentrated to give 2.95 g ofPreparatory Compound U tert-butyl2-(6-chloro-3-pyridinyl)-3-oxo-1-piperazinecarboxylate as a light yellowsolid. A portion was recrystallized from ethyl acetate to give mp168-70° C.; ¹HNMR (CDCl₃) δ 8.44 (d, 1H, J=2.7 Hz), 7.78 (br d, 1H),7.33 (d, 1H, J=8.5 Hz), 6.54 (br s, 1H), 5.70 (br s, 1H), 4.13 (m, 1H),3.53-3.57 (m, 1H), 3.31-3.39 (m, 1H), 3.19-3.28 (m, 1H), 1.45 (s, 9H);MS (ES+) m/z 312 ([M+H]⁺).

Example V Preparation of Preparatory Compound V

A solution of 312 mg (1.00 mmol) of Preparatory Compound U and 222 mg(1.00 mmol) of phosphorus pentasulfide in 4 mL of dry pyridine washeated at 80° C. for four hours and was allowed to cool. The contentswere added dropwise to 30 mL of cold water. Upon warming to roomtemperature over an hour a fine tan precipitate was present. The mixturewas cooled again in ice and the precipitate was collected and air-driedto give 152 mg (46%) of Preparatory Compound V tert-butyl2-(6-chloro-3-pyridinyl)-3-thioxo-1-piperazinecarboxylate; ¹HNMR (CDCl₃)δ 8.51 (br s and d, 2H, J=2.6 Hz), 7.78 (br d, 1H), 7.33 (d, 1H, J=8.2Hz), 6.17 (br s, 1H), 4.13 (m, 1H), 3.57 (m, 1H), 3.35-3.48 (m, 1H),3.23-3.27 (m, 1H), 1.47 (s, 9H); MS (ES+) m/z 328 ([M+H]⁺).

Example W Preparation of Preparatory Compound W

A solution of 970 mg (2.96 mmol) of Preparatory Compound V and 3 mL oftrifluoroacetic acid in 15 mL of dichloromethane was stirred at roomtemperature for three hours. The solution was concentrated in vacuo andthe residue was dissolved in dichloromethane and was added to 20 mL of15% aqueous potassium carbonate. The aqueous phase was then extractedonce with dichloromethane and the combined organics were dried overpotassium carbonate. Concentration gave 670 mg which was chromatographedon silica gel (230-400 mesh) using 9/1 dichloromethane/methanolcontaining 5% ammonium hydroxide to afford 260 mg of PreparatoryCompound W 3-(6-chloro-3-pyridinyl)-2-piperazinethione; ¹HNMR (CDCl₃) δ8.54 (br s, 1H), 8.48 (d, 1H, J=2.4 Hz), 7.90 (dd, 1H, J=8.3 Hz, andJ=2.6 Hz), 7.32 (d, 1H, J=8.2 Hz), 4.92 (s, 1H), 3.51-3.58 (m, 1H),3.40-3.48 (m, 1H), 3.15-3.20 (m, 2H), 2.07 (br s, 1H); MS (ES+) m/z 228([M+H]⁺).

Example 1 Preparation of Compound 1

The oily residue containing Preparatory Compound D from Example D wasdissolved in 6 mL of nitromethane (pre-treated with neutral alumina andfiltered through a membrane) and heated at 100° C. for 24 hours. Theclear orange solution was then partitioned between water and ether andthe organic layer dried over sodium sulfate. The solvent was removedunder reduced pressure and the brown residue purified further by columnchromatography on silica gel using 80% ethyl acetate/petroleum ether asthe eluent. The solvent was removed under reduced pressure to yield 110mg (26% over 2 steps) of Compound 1,(1Z)-3-(6-chloro-3-pyridinyl)-N-methyl-1-nitro-1-propen-2-amine, as alight yellow brown solid: mp 124-125° C.; ¹H NMR (CDCl₃) δ 8.32 (d,J=2.6 Hz, 1H), 7.54 (dd, J=2.6 and 7.8 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H),6.50 (s, 1H), 3.60 (s, 2H), 3.02 (d, J=5.6 Hz, 3H) ppm. MS: (ES−)m/z=226 (M−1).

Example 1A Alternative Preparation of Compound 1

A solution of 240 mg (1.12 mmol) of Compound 5 in 12 mL of 2.0 Mmethylamine in tetrahydrofuran was stirred at room temperature (about22° C.) overnight. The solution was concentrated to an oil which waschromatographed on silica gel (230-400 mesh) using 95/5dichloromethane/methanol as eluent to afford 248 mg (97%) of Compound 1.

Example 2 Preparation of Compound 2

The oily residue containing Preparatory Compound J from Example J wasdissolved in 4 mL of a 10:1 mixture of nitromethane anddimethylsulfoxide (pre-treated with neutral alumina and filtered througha membrane) and heated at 115° C. for 36 hours. The clear orangesolution was then partitioned between water and ether and the organiclayer dried over sodium sulfate. The solvent was removed under reducedpressure and the brown residue purified further by column chromatographyon silica gel using 50% ethyl acetate/petroleum ether as the eluent. Thesolvent was removed under reduced pressure to yield 22 mg (11% over 2steps) of Compound 2,(1Z)-3-(6-chloro-3-pyridinyl)-N-methyl-1-nitro-1-buten-2-amine, as alight yellow solid: mp 144-145° C.; ¹H NMR (CDCl₃) δ 8.34 (d, J=2.6 Hz,1H), 7.55 (dd, J=2.6 and 7.8 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 6.65 (s,1H), 4.00 (q, J=7.6 Hz, 1H), 2.98 (d, J=5.7 Hz, 3H), 1.52 (d, J=7.6 Hz,3H) ppm. MS: (EI-DIP) m/z 241 (M+).

Example 2A Alternative Preparation of Compound 2

A solution of 610 mg (2.68 mmol) of Compound 6 in 20 mL of 2.0 Mmethylamine in tetrahydrofuran was heated at 40° C. for 40 hours, wasconcentrated to a residue and was dissolved in dichloromethane and driedover magnesium sulfate. Concentration gave 720 mg of an oil which waschromatographed on silica gel (230-400 mesh) using 95/5dichloromethane/methanol as eluent to afford 472 mg (73%) of Compound 2.

Example 3 Preparation of Compound 3

Preparatory Compound D was generated as described above from 580 mg(3.15 mmol) of Preparatory Compound C and 142 mg (3.55 mmol) of 60%sodium hydride. The resulting oily residue was dissolved in 15 mL of dryethanol and treated with 540 mg (12.9 mmol) of cyanamide under anitrogen atmosphere. After stirring for 30 minutes at room temperature(about 22° C.), thin layer chromatography and reverse-phase HPLCindicated the reaction was complete. The solvent was removed underreduced pressure, the residue dissolved in dichloromethane and driedover sodium sulfate. The solvent was removed under reduced pressureagain and the residue purified further by column chromatography onsilica gel using 80% ethyl acetate/petroleum ether as the eluent. Thesolvent was removed under reduced pressure to yield 385 mg (60% over 2steps) of Compound 3,(1Z)-2-(6-chloro-3-pyridinyl)-N-cyano-N-methylethanimidamide, as a paleyellow solid: mp 136-138° C.; ¹H NMR (CDCl₃) δ 8.32 (d, J=2.6 Hz, 1H),7.68 (dd, J=2.6 and 7.8 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 3.96 (s, 2H),2.90 (d, J=5.1 Hz, 3H) ppm. MS: (EI-DIP) m/z 207 (M+). Anal. Calcd forC₉H₉ClN₄: C, 51.8; H, 4.35; N, 26.9. Found: C, 51.9; H, 4.35; N, 26.8.

Example 4 Preparation of Compound 4

Cyanamide (0.330 g, 0.00789 mol) was added to a solution of Compound J(0.450 g, 0.00197 mol) in 10 mL absolute ethanol under a nitrogenatmosphere. The mixture was heated at 78° C. for 0.5 hours, thenconcentrated in vacuo. The residue was dissolved in dichloromethane andrefrigerated for 16 hours, during which time a precipitate formed. Theprecipitate was removed by vacuum filtration. The filtrate was driedover magnesium sulfate and concentrated to a yellow oil. The oil wasrecrystallized in boiling ethyl acetate to yield 0.177 g (40%) ofCompound 4, (1Z)-2-(6-chloro-3-pyridinyl)-N′-cyano-Nmethylpropanimidamide, as a yellow solid. m.p. 170.5-173° C. ¹H NMR(DMSO-d₆) δ 8.73 (br s), 83.8 (d, 1H, J=2.6 Hz), 7.79 (dd, 1H, J=2.7 Hzand 8.6 Hz), 7.54 (d, 1H, J=8.5 Hz), 4.28 (q, 1H, J=7.2 Hz), 2.76 (s,3H), 1.58 (d, 3H, J=7.3 Hz). MS (ESI) m/z 225 ([M+H]⁺+2, 37), 223([M+H]⁺, 100), 196 (30).

Example 5 Preparation of Compound 5

A solution of 9.7 g (48.8 mmol) of Preparatory Compound K in 325 mL of a50:50 solution of dimethylsulfoxide and nitromethane was heated at 115°C. overnight. After 17 hours nitromethane and other volatiles wereremoved in vacuo and the solution was then added dropwise to 1 L of icewater and was then extracted six times with 450 mL of ethyl ether. Thecombined extracts were dried over magnesium sulfate while the aqueousphase was continuously extracted with ether overnight which was thendried over magnesium sulfate. Concentration of both dried extractsafforded 10.95 g which was triturated under dichloromethane overnight.The mixture was cooled in ice and was filtered to afford 3.2 g (31%) ofCompound 5, (1Z)-3-(6-chloro-3-pyridinyl)-1-nitro-1-propen-2-amine. Thefiltrate was concentrated to give 7.0 g which was chromatographed onsilica gel (230-400 mesh) to afford an additional 990 mg of Compound 5.

Example 6 Preparation of Compound 6

To a mixture of 611 mg (2.86 mmol) of Compound 5 in 4 mL of drytetrahydrofuran cooled in a dry ice/isopropanol bath was added dropwisevia syringe 5.7 mL (5.7 mmol) of a 1.0 M solution of lithiumbis-(trimethylsilyl)amide in tetrahydrofuran. The contents were stirredat the bath temperature (about −78° C.) for 3 hours and were thentreated dropwise with 0.7 mL (11.2 mmol) of methyl iodide over a tenminute period. The mixture was then allowed to warm to room temperature(about 22° C.) overnight. The mixture was cooled in ice and was treatedwith 5 mL of saturated ammonium chloride was extracted twice withdichloromethane, and the combined extracts were dried with magnesiumsulfate. Concentration gave 602 mg of a residue which waschromatographed on silica gel (230-400 mesh) using 96/4dichloromethane/methanol as eluent to afford 309 mg (47%) of Compound 6,(1Z)-3-(6-chloro-3-pyridinyl)-1-nitro-1-buten-2-amine, mp 83-85° C.

Example 7 Preparation of Compound 7

Compound 9 (0.26 g, 0.001 mol) was dissolved in anhydroustetrahydrofuran (7 mL) and cooled to −78° C. N-butyllithium (2.5 M inhexanes, 0.8 mL, 0.002 mol) was added dropwise to the solution. Theresulting mixture was stirred for 30 minutes. at −78° C., theniodomethane (0.91 g, 0.0064 mol) was added dropwise to the solution. Themixture was allowed to slowly warm to room temperature (about 22° C.)and stirred overnight. The flask was then cooled to 0° C. Saturatedaqueous ammonium chloride was added. The mixture was extracted threetimes with dichloromethane, and the combined extracts were dried overmagnesium sulfate. The solution was concentrated in vacuo, and theresidue was purified by column chromatography using 55% hexanes/ethylacetate as eluents. Fractions containing the desired product werecollected and concentrated in vacuo to afford 0.0155 g (5%) of theCompound 7,(N-{(Z)-1-[1-(5,6-dichloropyridin-3-yl)ethyl]-2-nitrovinyl}-N-methylamine),as a yellow solid m.p. 122-123° C. ¹H NMR δ 8.23 (d, 1H, J=2.1 Hz), 7.66(d, 1H, J=2.3 Hz), 6.63 (s, 1H), 4.01 (q, 1H, J=7.2 Hz), 2.99 (d, 3H,J=5.6 Hz), 1.53 (d, 3H, J=7.1 Hz). MS (ESI) m/z 278 ([M−H+4]⁺, 14), 276([M−H+2]⁺, 59), 274 ([M−H]⁺, 100) 215 (75), 176 (30).

Example 8 Preparation of Compound 8

The yellow syrup from Example O containing Preparatory Compound O wasdissolved in 10 mL of isopropanol and treated with 5 mL of 1.0Mmethylamine in tetrahydrofuran. The mixture was heated at 50° C. for 20minutes. The solvent was removed under reduced pressure and the residuepurified by column chromatography on silica gel using 50-80% ethylacetate/petroleum ether as the eluent. After the solvent was removedunder reduced pressure, the residue was dissolved in acetonitrile andpassed through a membrane filter to remove the resulting solids. Thesolvent was removed under reduced pressure to yield 65 mg (10% over 2steps) of Compound 8,(1Z)-3-(6-chloro-3-pyridinyl)-N-methyl-1-nitro-1-penten-2-amine, as alight yellow solid: mp 93-94° C.; ¹H NMR (CDCl₃) δ 10.3 (bs, 1H), 8.30(d, J=2.5 Hz, 1H), 7.58 (dd, J=2.5 and 7.5 Hz, 1H), 7.35 (d, J=7.5 Hz,1H), 6.74 (s. 1H) 3.65 (t, J=7.9 Hz, 1H), 3.00 (d, J=5.9 Hz, 3H)), 2.16(m, 1H), 1.80 (m, 1H) 1.00 (t, J=7.9 Hz, 3H) ppm. MS: (ES−) m/z 254(M−1).

Example 9 Preparation of Compound 9

A solution of 2 M methylamine in tetrahydrofuran (7 mL, 0.014 mol) wasadded to a flask containing Compound 30 (0.231 g, 0.00093 mol). Theflask was capped and stirred at room temperature (about 22° C.)overnight. The resulting mixture was concentrated in vacuo to yieldCompound 9,N-{(Z)-1-[(5,6-dichloropyridin-3-yl)methyl]-2-nitrovinyl}-N-methylamine,as a dark yellow oil (0.260 g). ¹H NMR δ 8.24 (d, 1H, J=2.3 Hz), 7.72(d, 1H, J=2.3 Hz), 6.51 (s, 1H), 3.67 (s, 2H), 3.05 (d, 3H, J=5.0 Hz).

Example 10 Preparation of Compound 10

Ethylamine (2.0 M in tetrahydrofuran, 9.2 mL, 0.0184 mol) was added to aflask containing Compound 30 (0.299 g, 0.00121 mol) under nitrogen. Themixture was stirred at room temperature (about 22° C.) overnight. Themixture was concentrated in vacuo and the residue was dissolved in ethylacetate. The solution was washed with brine and dried over magnesiumsulfate, then concentrated in vacuo. The residue was purified by columnchromatography using 5% methanol/dichloromethane as eluents. Fractionscontaining the desired product were collected and concentrated in vacuoto afford 0.276 g (83%) of Compound 10,N-{(Z)-1-[(5,6-dichloropyridin-3-yl)methyl]-2-nitrovinyl}-N-ethylamine,a light orange solid. m.p. 126.5-128° C. ¹H NMR δ 9.95 (br s, 1H), 8.21(d, 1H, J=2.3 Hz), 7.66 (d, 1H, J=2.3 Hz), 6.48 (s, 1H), 3.60 (s, 2H),3.33 (q, 2H, J=6.9 Hz), 1.28 (t, 3H, J=7.3 Hz). MS (ESI) m/z 280([M+H+4]⁺, 10), 278 ([M+H+2]⁺, 65), 276 ([M+H]⁺, 100), 217 (29), 215(46). Anal. Calcd. for C₁₀H₁₁Cl₂N₃O₂: C, 43.50; H, 4.02; N, 15.22.Found: C, 43.77; H, 4.02; N, 14.94.

Example 11 Preparation of Compound 11

A round-bottomed flask charged with Compound 10 (0.202 g, 0.00073 mol)in tetrahydrofuran (5 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 1.6 mL., 0.0016mol) was added dropwise to the mixture, which was then stirred at −78°C. for 30 minutes. Iodomethane (4.56 g, 0.03213 mol) was added dropwise.The mixture was allowed to slowly warm to room temperature (about 22°C.) and stirred overnight. The mixture was then cooled to 0° C. andtreated with saturated aqueous ammonium chloride solution (8 mL). Thesolution was extracted two times with dichloromethane. The extracts werecombined and dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by column chromatography using 3%methanol/dichloromethane as eluents. Fractions containing the desiredproduct were combined and concentrated in vacuo to afford an orange oil.The oil was triturated under diethyl ether to yield 0.109 g (52%) ofCompound 11,N-{(Z)-1-[1-(5,6-dichloropyridin-3-yl)ethyl]-2-nitrovinyl}-N-ethylamine,as a yellow-orange solid. ¹H NMR δ 10.15 (br s, 1H), 8.22 (d, 1H, J=2.3Hz), 7.65 (d, 1H, J=2.3 Hz), 6.60 (s, 1H), 3.99 (q, 1H, J=7.1 Hz), 3.31(m, 2H), 1.53 (d, 3H, J=7.1 Hz), 1.28 (t, 3H, J=7.2 Hz).

Example 12 Preparation of Compound 12

Ethylamine (2.0 M in tetrahydrofuran, 18 mL, 0.036 mol) was added to aflask containing Compound 5 (0.499 g, 0.00235 mol) under nitrogen. Themixture was stirred at room temperature (about 22° C.) overnight. Themixture was then concentrated in vacuo. The residue was triturated underdichloromethane and concentrated again. The residue was purified bycolumn chromatography using 3% methanol/dichloromethane as eluents.Fractions containing Compound 12 were combined and concentrated in vacuoto afford an orange oil. The oil was triturated under diethyl ether toyield 0.53 g (94%) of Compound 12,N-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}-N-ethylamine. ¹HNMR δ 9.97 (br s, 1H), 8.29 (dd, 1H, J=0.7 Hz and J=2.6 Hz), 7.53 (dd,1H, J=2.6 Hz and J=8.2 Hz), 7.36 (d, 1H, J=8.5 Hz), 6.48 (s, 1H), 3.59(s, 2H), 3.32 (q, 2H, J=7.2 Hz), 1.26 (t, 3H, J=7.3 Hz). MS (ESI) m/z243 ([M+2]⁺, 7), 241 ([M]⁺, 22), 194 (100), 179 (52), 126 (50).

Example 13 Preparation of Compound 13

Propylamine (1.09 g, 0.0185 mol) was added to a flask containingCompound 30 (0.312 g, 0.00126 mol) in tetrahydrofuran (8 mL) undernitrogen. The mixture was stirred overnight. The solution was thenconcentrated in vacuo to obtain a dark orange oil. The residue waspurified by column chromatography using 3% methanol/dichloromethane aseluents. Fractions containing the desired product were combined andconcentrated in vacuo to afford an orange solid. The solid wastriturated under diethyl ether to yield 0.197 g (54%) of Compound 13,N-{(Z)-1-[(5,6-dichloropyridin-3-yl)methyl]-2-nitrovinyl}-N-propylamine,as an orange solid. ¹H NMR δ 10.04 (br s, 1H), 8.20 (d, 1H, J=2.1 Hz),7.64 (d, 1H, J=2.1 Hz), 6.48 (s, 1H), 3.58 (s, 2H), 3.23 (q, 2H, J=6.6Hz), 1.71-1.63 (m, 2H), 0.98 (t, 3H, J=7.3 Hz).

Example 14 Preparation of Compound 14

Propylamine (2.12 g, 0.0358 mol) was added to a flask containingCompound 5 (0.500 g, 0.00236 mol) in tetrahydrofuran (15 mL) undernitrogen. The mixture was stirred overnight. The solution was thenconcentrated in vacuo to obtain a dark brown oil. The residue waspurified by column chromatography using 3% methanol/dichloromethane aseluents. Fractions containing the desired product were combined andconcentrated in vacuo to yield 0.47 g (78%) of Compound 14,N-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}-N-propylamine, asan orange solid. ¹H NMR δ 10.08 (br s, 1H), 8.30 (d, 1H, J=2.4 Hz), 7.53(dd, 1H, J=2.4 Hz and J=8.6 Hz), 7.36 (d, 1H, J=8.2 Hz), 6.48 (s, 1H),3.58 (s, 2H), 3.23 (q, 2H, 6.6 Hz), 1.69-1.50 (m, 2H), 0.96 (t, 3H,J=7.4 Hz). MS (ESI) m/z 257 ([M+2]⁺, 8), 255 ([M]⁺, 31), 208 (90), 179(94), 126 (100).

Example 15 Preparation of Compound 15

A round-bottomed flask charged with Compound 12 (0.430 g, 0.00178 mol)in tetrahydrofuran (12 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 3.8 mL., 0.0038mol) was added dropwise to the mixture, which was then stirred at −78°C. for 30 minutes. Iodomethane (4.56 g, 0.03213 mol) was added dropwise.The mixture was allowed to slowly warm to room temperature and stirredovernight. The mixture was then cooled to 0° C. and treated withsaturated aqueous ammonium chloride solution (20 mL). The mixture wasextracted with dichloromethane. The extract was then washed two timeswith water and dried over magnesium sulfate. The solution wasconcentrated in vacuo to a dark brown oil. The oil was purified bycolumn chromatography using 20% ethyl acetate/hexanes as eluents.Fractions containing the desired product were collected and concentratedin vacuo to yield 0.159 g (35%) of Compound 15,N-{(Z)-1-[1-(6-chloropyridin-3-yl)ethyl]-2-nitrovinyl}-N-ethylamine, asan amber oil. ¹H NMR δ 10.18 (br s, 1H), 8.32 (d, 1H, J=2.6 Hz), 7.55(dd, 1H, J=2.6 Hz and 8.3 Hz), 7.35 (d, 1H, J=8.3 Hz), 6.63 (s, 1H),3.98 (q, 1H, J=7.2 Hz), 3.45-3.12 (m, 2H), 1.52 (d, 3H, J=7.1 Hz), 1.25(t, 3H, J=7.22 Hz). Anal. Calcd. for C₁₁H₁₄ClN₃O: C, 51.67; H, 5.52; N,16.43. Found: C, 51.49; H, 5.44; N, 16.18.

Example 16 Preparation of Compound 16

A round-bottomed flask charged with Compound 14 (0.411 g, 0.00162 mol)in tetrahydrofuran (12 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 3.5 mL., 0.0035mol) was added dropwise to the mixture, which was then stirred at −78°C. for 1 hour. Iodomethane (4.56 g, 0.03213 mol) was added dropwise. Themixture was allowed to slowly warm to room temperature and stirredovernight. The mixture was then cooled to 0° C. and treated withsaturated aqueous ammonium chloride solution (20 mL). The mixture wasextracted with dichloromethane. The extract was then washed two timeswith water and dried over magnesium sulfate. The solution wasconcentrated in vacuo to a dark orange oil. The oil was purified bycolumn chromatography using first 15% ethyl acetate/hexanes and then agradient from 100% dichloromethane to 3% methanol/dichloromethane aseluents. Fractions containing the desired product were collected andconcentrated in vacuo to yield 0.090 g (21%) of Compound 16,N-{(Z)-1-[1-(6-chloropyridin-3-yl)ethyl]-2-nitrovinyl}-N-propylamine, asan amber oil. ¹H NMR δ 10.32 (br s, 1H), 8.32 (d, 1H, J=2.6 Hz), 7.55(dd, 1H, J=2.6 Hz and J=8.3 Hz), 7.36 (d, 1H, J=8.2 Hz), 6.63 (s, 1H),3.99 (q, 1H, J=7.2), 3.42-3.06 (m, 2H), 1.68-1.56 (m, 2H), 1.52 (d, 3H,J=7.1 Hz), 0.96 (t, 3H, J=7.39 Hz).

Example 17 Preparation of Compound 17

A mixture of 440 mg (2.06 mmol) of Compound 5 and 479 mg (5.73 mmol) ofmethoxylamine hydrochloride in 3 mL of tetrahydrofuran was treated with580 mg (5.73 mmol) of triethylamine. The mixture was stirred at roomtemperature (about 22° C.) for three days and was filtered. The filtratewas concentrated to give 510 mg of a residue which was chromatographedon silica gel using 95/5 dichloromethane/ethyl acetate as eluent to give356 mg (71%) of Compound 17,2-chloro-5-[(2Z)-2-(methoxyamino)-3-nitro-2-propenyl]pyridine, as anoil; ¹H NMR 8 (obtained as a mixture of syn and anti isomers, data givenfor predominant isomer) 3.82 (s, 2H), 4.02 (s, 3H), 4.95 (s, 2H), 7.32(d, 1H, J=9.0 Hz), 7.47 (dd, 1H, J=8.5 Hz and J=2.5 Hz), 8.24 (d, 1H,J=2.6 Hz); MS (DIP) m/z 245 ([M+2]⁺, 3), 243 (M+, 10), 166 (100), 126(97). Anal. Calcd. for C₉H₁₀ClN₃O₃: C, 44.36; H, 4.14; N, 17.23. Found:C, 44.29; H, 4.16; N, 17.33.

Example 18 Preparation of Compound 18

A round-bottomed flask charged with Compound 5 (0.600 g, 0.00283 mol) intetrahydrofuran (16 mL) was treated with aminoacetaldehyde dimethylacetal (4.63 g, 0.04406 mol). The flask was capped, and the mixture wasstirred at room temperature (about 22° C.) overnight. The solution wasconcentrated in vacuo and purified by column chromatography using 3%methanol/dichloromethane as eluents. Fractions containing the desiredproduct were collected and concentrated in vacuo to yield 0.658 g (77%)of Compound 18,N-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}-N-(2,2-dimethoxyethyl)amine,as a greenish oil. ¹H NMR δ 10.01 (brs, 1H), 8.29, (d, 1H, J=2.6 Hz),7.53 (dd, 1H, J=2.52 Hz and 8.1 Hz), 7.35 (d, 1H, J=8.2 Hz), 6.46 (s,1H), 4.38 (t, 1H, J=5.1 Hz), 3.64 (s, 2H), 3.42 (s, 6H), 3.40-3.35 (m,2H). Anal. Calcd. for C₁₂H₁₆ClN₃O₄: C, 47.77; H, 5.34; N, 1.93. Found:C, 47.99; H, 5.32; N, 13.79.

Example 19 Preparation of Compound 19

A round-bottomed flask charged with Compound 5 (0.595 g, 0.00280 mol) intetrahydrofuran (17 mL) was treated with isopropylamine (2.53 g, 0.0429mol). The flask was capped, and the mixture was stirred at roomtemperature (about 22° C.) for 72 hours. The solution was concentratedin vacuo and purified by column chromatography using 2%methanol/dichloromethane as eluents. Fractions containing the desiredproduct were collected and concentrated in vacuo to yield 0.427 g (56%)of Compound 19,N-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}-N-isopropylamine,as a yellow solid. m.p. 89.5-93° C. ¹H NMR δ 10.03 br s, 1H), 8.30 (d,1H, J=2.6 Hz), 7.54 (dd, 1H, J=2.3 Hz and J=7.9 Hz), 7.36 (d, 1H, J=8.3Hz), 6.44 (s, 1H), 3.81-3.73 (m, 1H), 3.59 (s, 2H), 1.23 (d, 6H, J=6.4Hz). MS (ESI) m/z 258 ([M+2]⁺, 35), 256 ([M]⁺, 100), 153 (20).

Example 20 Preparation of Compound 20

To a solution of Compound 1 (0.227 g, 1.0 mmol) in tetrahydrofuran (10mL) cooled in a dry ice-acetone bath was added 1.0M lithiumbis(trimethylsilyl)amide (2.2 mL, 2.2 mmol) dropwise under nitrogen in10 minutes and the mixture was stirred for 3 hours. Methyl disulfideliquid (0.45 mL, 5 mmol) was added via a syringe. Dry ice-acetone bathwas removed and the temperature was allowed to rise to room temperature(about 22° C.). The reaction was quenched with saturated ammoniumchloride aqueous solution, extracted with methylene chloride. Theorganic phase was washed with water and brine, dried over anhydroussodium sulfate, concentrated and purified on silica gel column by flashchromatography to give one-spot product. A further purification wascarried out on preparative HPLC to give 0.11 g of Compound 20,(1Z)-3-(6-chloro-3-pyridinyl)-N-methyl-3-(methylthio)-1-nitro-1-propen-2-amine,as a light yellow oil in 40% yield.

Example 21 Preparation of Compound 21

By following the procedure described for Compound 20, 0.227 g ofCompound 1 (1.0 mmol) was deprotonated by 1.0 M lithiumbis(trimethylsilyl)amide (2.2 mL, 2.2 mmol) and reacted withN-fluorodibenzenesulfonamide (0.30 g, 4 mmol) to give 0.104 g Compound21,(1Z)-3-(6-chloro-3-pyridinyl)-3-fluoro-N-methyl-1-nitro-1-propen-2-amine,as brownish oil in 42% yield.

Example 22 Preparation of Compound 22

Using the procedure described for Compound 20, the same amount ofCompound 1 was reacted with hexachloroethane (0.94 g, 4.0 mmol) to give0.224 g of Compound 22,(1Z)-3,3-dichloro-3-(6-chloro-3-pyridinyl)-N-methyl-1-nitro-1-propen-2-amine,as a yellowish solid in 76% yield.

Example 23 Preparation of Compound 23

A mixture of Compound 1 (0.113 g, 0.5 mmol), N-bromosucciniamide (0.104g, 0.6 mmol) and sodium methoxide (0.030 g, 0.55 mmol) in CCl₄ (50 mL)was stirred at room temperature (about 22° C.) overnight. The mixturewas then washed with water and brine, dried over anhydrous sodiumsulfate, purified on silica gel (30% ethylacetate in dichloromethane) togive 0.041 g of Compound 23,(1E)-1-bromo-3-(6-chloro-3-pyridinyl)-N-methyl-1-nitro-1-propen-2-amine,in 27% yield.

Example 24 Preparation of Compound 24

Using the procedure described for Compound 23, the same amount ofCompound 1 was reacted with sodium thiomethoxide (0.039 g, 0.55 mmol) togive 0.030 g of Compound 24,(1E)-3-(6-chloro-3-pyridinyl)-N-methyl-1-(methylthio)-1-nitro-1-propen-2-amine,as a yellowish oil in 19% yield.

Example 25 Preparation of Compound 25

Compound 6 (0.288 g, 0.00133 mol) was dissolved in tetrahydrofuran (9mL) and isopropylamine (10 mL) and heated at 35° C. for 120 hours. Theresulting mixture was cooled and concentrated in vacuo to a yellow oil,which was purified by column chromatography using 25% ethylacetate/hexanes as eluents. Fractions containing the desired productwere collected and concentrated in vacuo to a clear oil, which wastriturated under diethyl ether to obtain 0.0699 g (19%) of Compound 25,N-{(Z)-1-[1-(6-chloropyridin-3-yl)ethyl]-2-nitrovinyl}-N-isopropylamine,as an off-white solid. m.p. 116-118° C. ¹H NMR δ 10.29 (br s, 1H), 8.32(d, 1H, J=2.6 Hz), 7.54 (dd, 1H, J=2.5 Hz and J=8.3 Hz), 7.35 (d, 1H,J=8.2 Hz), 6.56 (s, 1H), 4.00 (q, 1H, J=7.2 Hz), 3.84-3.76 (m, 1H), 1.54(d, 3H, J=7.1 Hz), 1.31 (d, 3H, J=6.4 Hz), 1.10 (d, 3H, J=6.3 Hz). MS(ESI) m/z 272 ([M+H+2]⁺, 38), 270 ([M+H]⁺, 100), 252 (16), 223 (27), 167(23). Anal. Calcd. for C₁₂H₁₆ClN₃O₂: C, 53.44; H, 5.98; N, 15.58. Found:C, 53.64; H, 6.11; N, 15.24.

Example 26 Preparation of Compound 26

A round-bottomed flask charged with Compound 5 (0.611 g, 0.00288 mol) intetrahydrofuran (2 mL) was treated with benzylamine (0.352 g, 0.00328mol). The flask was capped, and the mixture was stirred at roomtemperature (about 22° C.) overnight. The temperature was then increasedto 40° C., and the solution was stirred for an additional 24 hours atthis temperature. The flask was cooled to room temperature (about 22°C.). The material was dissolved in dichloromethane and washed withbrine. The brine layer was extracted with dichloromethane once, then thecombined organic phases were dried over magnesium sulfate. The solutionwas concentrated in vacuo to give a dark brown solid, which wastriturated under cold diethyl ether to yield 0.629 g (72%) of Compound26, N-benzyl-N-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}amine,as a tan solid. m.p. 112-114.5° C. ¹H NMR δ 10.33 (br s, 1H), 8.26 (d,1H, J=2.4 Hz), 7.49 (dd, 1H, J=2.4 Hz and 8.2 Hz), 7.42-7.26 (m, 5H),7.18 (d, 1H, J=5.9 Hz), 6.52 (s, 1H), 4.47 (d, 2H, J=6.4 Hz), 3.58 (s,1H). Anal Calcd. for C₁₅H₁₄ClN₃O₂: C, 59.31; H, 4.65; N, 13.83. Found:C, 59.03; H, 4.79; N, 13.64.

Example 27 Preparation of Compound 27

A round-bottomed flask charged with Compound 5 (0.641 g, 0.00302 mol)was treated with cyclopropylamine (2.47 g, 0.04329 mol). The flask wascapped, and the mixture was stirred at room temperature (about 22° C.)overnight. The mixture was concentrated in vacuo to give a dark brownoil, which was dissolved in dichloromethane and washed with brine. Thebrine layer was extracted with dichloromethane once, then the combinedorganic phases were dried over magnesium sulfate. The solution wasconcentrated in vacuo to give a dark orange oil, which was purified bycolumn chromatography using 20% ethyl acetate/dichloromethane aseluents. Fractions containing the desired compound were collected andconcentrated in vacuo to yield 0.450 g (59%) of Compound 27,N-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}-N-cyclopropylamine,as a yellow oil.

Example 28 Preparation of Compound 28

By following the procedure described for Compound 20, 0.227 g ofCompound 1 (1.0 mmol) was deprotonated by lithiumbis(trimethylsilyl)amide (2.2 mL, 2.2 mmol) and then reacted withpropargyl bromide (0.65 g, 5.0 mmol) to give 0.065 g of Compound 28,(1Z)-3-(6-chloro-3-pyridinyl)-N-methyl-1-nitro-1-hexen-5-yn-2-amine, asa yellowish foam upon drying under vacuum in a yield of 24%.

Example 29 Preparation of Compound 29

A round-bottomed flask charged with Compound 27 (0.380 g, 0.00150 mol)in tetrahydrofuran (10 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 3.4 mL., 0.00340mol) was added dropwise to the mixture, which was then stirred at −78°C. for 2 hours. Iodomethane (4.56 g, 0.03213 mol) was added dropwise.The mixture was allowed to slowly warm to room temperature and stirredovernight. The mixture was then cooled to 0° C. and treated withsaturated aqueous ammonium chloride solution (18 mL). The mixture wasextracted with dichloromethane. The extract was then washed two timeswith water and dried over magnesium sulfate. The solution wasconcentrated in vacuo to a dark orange oil. The oil was purified bycolumn chromatography using 5% ethyl acetate/dichloromethane as eluents.Fractions containing the desired product were collected and concentratedin vacuo to afford a yellow oil, which was triturated under cold ethylether to yield 0.035 g (9%) of Compound 29,N-{(Z)-1-[1-(6-chloropyridin-3-yl)ethyl]-2-nitrovinyl}-N-cyclopropylamine,as a yellow powder.

Example 30 Preparation of Compound 30

Dimethylsulfoxide (23 mL) and nitromethane (23 mL) were combined anddried for 4 hours over alumina. The mixture was filtered into a flaskcontaining Preparatory Compound R (0.93 g, 0.00401 mol). The flask wasfitted with a reflux condenser and heated at 115° C. overnight. Themixture was cooled to room temperature (about 22° C.) and concentratedin vacuo. The residue was added dropwise to ice, then extracted fourtimes with 400 mL diethyl ether. The extracts were combined and driedover magnesium sulfate, then concentrated in vacuo. The residue waspurified by column chromatography using 20% ethylacetate/dichloromethane as eluents. Fractions containing the desiredproduct were collected and concentrated in vacuo to afford 0.300 g (30%)of Compound 30,(Z)-1-[(5,6-dichloropyridin-3-yl)methyl]-2-nitrovinylamine, as a yellowsolid. ¹H NMR (DMSO-d₆) δ 9.05 (br s, 1H), 8.78 (br s, 1H), 8.42 (d, 1H,J=2.1 Hz), 8.17 (d, 1H, J=2.1 Hz), 6.72 (s, 1H), 3.55 (s, 2H).

Example 31 Preparation of Compound 31

A round-bottomed flask charged with Compound 26 (0.545 g, 0.00180 mol)in tetrahydrofuran (10 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 4.0 mL., 0.00400mol) was added dropwise to the mixture, which was then stirred at −78°C. for 2 hours. Iodomethane (4.56 g, 0.03213 mol) was added dropwise.The mixture was allowed to slowly warm to room temperature and stirredovernight. The mixture was then cooled to 0° C. and treated withsaturated aqueous ammonium chloride solution (22 mL). The mixture wasextracted with dichloromethane. The extract was then washed two timeswith water and dried over magnesium sulfate. The solution wasconcentrated in vacuo to a dark orange oil. The oil was purified bycolumn chromatography using 50% ethyl acetate/hexanes as eluents.Fractions containing the desired product were collected and concentratedin vacuo to afford a yellow oil, which was triturated under ethyl etherto yield 0.175 g (31%) of Compound 31,N-benzyl-N-{(Z)-1-[1-(6-chloropyridin-3-yl)ethyl]-2-nitrovinyl}amine, asa yellow powder. m.p. 77-81° C.

Example 32 Preparation of Compound 32

A round-bottomed flask charged with Compound 5 (0.400 g, 0.00187 mol)was dissolved in tetrahydrofuran (10 mL) and treated with allylamine(1.64 g, 0.02880 mol). The flask was capped, and the mixture was stirredat room temperature (about 22° C.) for 3 days. The mixture wasconcentrated in vacuo to give a dark brown oil. The oil was purified bycolumn chromatography using 30% ethyl acetate/dichloromethane aseluents. Fractions containing the desired product were combined andconcentrated in vacuo to obtain a clear oil, which gradually solidifiedand colored to afford 0.295 mg (62.5%) of Compound 32,N-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}prop-2-en-1-amine,as a light orange solid. m.p. 84-88.5° C.

Example 33 Preparation of Compound 33

A round-bottomed flask charged with Compound 5 (0.492 g, 0.00232 mol)was treated with isobutylamine (2.47 g, 0.04329 mol). The flask wascapped, and the mixture was stirred at room temperature (about 22° C.)overnight. The mixture was concentrated in vacuo to give a dark solid,which was dissolved in dichloromethane and washed with brine. Thesolution was dried over magnesium sulfate and concentrated in vacuo toafford 0.484 g (78%) of Compound 33,N-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}-N-isobutylamine,as a tan solid. m.p. 86-92.5° C.

Example 34 Preparation of Compound 34

By following the procedure described for Compound 20, 0.227 g ofCompound 1 (1.0 mmol) was deprotonated by lithiumbis(trimethylsilyl)amide (2.1 mL, 2.1 mmol) and reacted with allylbromide (0.60 g, 5.0 mmol) to give 0.193 g of Compound 34,(1Z)-3-(6-chloro-3-pyridinyl)-N-methyl-1-nitro-1,5-hexadien-2-amine, asa brownish oil in 72% yield.

Example 35 Preparation of Compound 35

A solution of 1.00 g (4.68 mmol) of Compound 5 and 606 mg (4.39 mmol) of2-(2-aminoethoxy)pyridine [Tetrahedron, 44, 91 (1988)] in 5 mL oftetrahydrofuran was heated at 40° C. for 32 hours and was allowed tocool. The volatiles were removed in vacuo and the resulting oil waschromatographed on silica gel using 95/5 dichloromethane/methanol aseluent to give 1.1 g (75%) of Compound 35,(1Z)-3-(6-chloro-3-pyridinyl)-1-nitro-N-[2-(2-pyridinyloxy)ethyl]-1-propen-2-amine,as a white solid, mp 112-114.5° C.; ¹H NMR δ 3.63-3.69 (m, 4H), 4.48 (m,2H), 6.48 (s, 1H), 6.75 (d, 1H, J=8.4 Hz), 6.93 (m, 1H), 7.32 (d, 1H,J=8.4 Hz), 7.51 (dd, 1H, J=8.9 Hz and J=1.8 Hz), 7.61 (m, 1H), 8.15 (m,1H), 8.27 (d, 1H, J=2.4 Hz), 10.33 (br s, 1H); MS (ESI+) m/z 337([M+2+H]⁺, 42), 335 ([M+H]⁺, 100.

Example 36 Preparation of Compound 36

A round-bottomed flask charged with Compound 33 (0.411 g, 0.00153 mol)in tetrahydrofuran (8 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 3.4 mL., 0.00340mmol) was added dropwise to the mixture, which was then stirred at −78°C. for 0.5 hours. Iodomethane (4.56 g, 0.03213 mol) was added dropwise.The mixture was allowed to slowly warm to room temperature and stirredovernight. The mixture was then cooled to 0° C. and treated withsaturated aqueous ammonium chloride solution (18.5 mL). The mixture wasextracted with dichloromethane. The extract was then washed with waterand dried over magnesium sulfate. The solution was concentrated in vacuoto a dark orange oil. The oil was purified by column chromatographyusing a gradient from 100% dichloromethane to 10% ethylacetate/dichloromethane as eluents. Fractions containing the desiredproduct were collected and concentrated in vacuo to afford an orangeoil, which was triturated under ethyl ether to yield 0.244 g (56%) ofCompound 36,N-{(Z)-1-[1-(6-chloropyridin-3-yl)ethyl]-2-nitrovinyl}-N-isobutylamine,as a yellow solid. m.p. 87-92° C.

Example 37 Preparation of Compound 37

A round-bottomed flask charged with Compound 5 (0.737 g, 0.00348 mol)was treated with sec-butylamine (4.34 g, 0.05939 mol). The flask wascapped, and the mixture was stirred at room temperature (about 22° C.)for 36 hours, then heated at 50° C. for an additional 8 hours. Themixture was brought up in dichloromethane, washed with saturated brinesolution, and dried over magnesium sulfate. It was then concentrated invacuo to yield 0.589 g (63%) of Compound 37,N-(sec-butyl)-N-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}amine,as a copper solid. m.p. 98.5-105.5° C.

Example 38 Preparation of Compound 38

A round-bottomed flask charged with Compound 37 (0.500 g, 0.00186 mol)in tetrahydrofuran (10 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 4.0 mL., 0.00400mol) was added dropwise to the mixture, which was then stirred at −78°C. for 0.5 hours. Iodomethane (4.56 g, 0.03213 mol) was added dropwise.The mixture was allowed to slowly warm to room temperature and stirredovernight. The mixture was then cooled to 0° C. and treated withsaturated aqueous ammonium chloride solution (17 mL). The mixture wasextracted with dichloromethane. The extract was then washed with waterand dried over magnesium sulfate. The solution was concentrated in vacuoto a dark orange oil. The oil was purified by column chromatographyusing a gradient from 100% dichloromethane to 10% ethylacetate/dichloromethane as eluents. Fractions containing the desiredproduct were collected and concentrated in vacuo to yield 0.298 g (57%)of Compound 38,N-(sec-butyl)-N-{(Z)-1-[1-(6-chloropyridin-3-yl)ethyl]-2-nitrovinyl}amine,as an orange solid. m.p. 88-92° C.

Example 39 Preparation of Compound 39

A round-bottomed flask charged with Compound 6 (0.145 g, 0.00064 mol) intetrahydrofuran (2 mL) was treated with allylamine (1.52 g, 0.00266mol). The flask was capped, and the mixture was stirred at roomtemperature (about 22° C.) overnight. The mixture was concentrated invacuo to afford a yellow oil, which was purified by columnchromatography using 10% ethyl acetate/dichloromethane as eluents.Fractions containing the desired compound were combined and concentratedin vacuo to yield 0.074 g (41%) of Compound 39,N-allyl-N-{(Z)-1-[1-(6-chloropyridin-3-yl)ethyl]-2-nitrovinyl}amine, asa yellow oil.

Example 40 Preparation of Compound 40

A round-bottomed flask charged with Compound 5 (0.750 g, 0.00354 mol) intetrahydrofuran (10 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 7.7 mL., 0.00770mol) was added dropwise to the mixture, which was then stirred at −78°C. for 0.5 hours. 1-iodopropane (3.49 g, 0.0205 mol) was added dropwise.The mixture was allowed to slowly warm to room temperature and stirredovernight. The mixture was then cooled to 0° C. and treated withsaturated aqueous ammonium chloride solution (32 mL). The mixture wasextracted with dichloromethane. The extract was then washed with waterand dried over magnesium sulfate. The solution was concentrated in vacuoto a dark brown oil. The oil was purified by column chromatography using20% ethyl acetate/dichloromethane as eluents. Fractions containing thedesired product were collected and concentrated in vacuo to yield 0.230g (25.5%) of Compound 40,(Z)-1-[1-(6-chloropyridin-3-yl)butyl]-2-nitrovinylamine, as a darkyellow oil.

Example 41 Preparation of Compound 41

A mixture of 300 mg (1.40 mmol) of Compound 5, 325 mg (1.40 mmol) ofcamphor sulfonic acid, and 131 mg (1.41 mmol) of aniline in 8 mL of1,2-dichloroethane was stirred at room temperature (about 22° C.) for 5days. The contents were diluted with dichloromethane and were washedtwice with saturated sodium bicarbonate and were dried (magnesiumsulfate). Concentration gave 400 mg which was chromatographed on silicagel using a dichloromethane/methanol gradient as eluent to afford 300 mg(74%) of Compound 41, A{(Z)-1-[(6-chloro-3-pyridinyl)methyl]-2-nitroethenyl}aniline, as a paleyellow solid, mp 143-145° C.; ¹H NMR δ 3.57 (s, 2H), 6.62 (s, 1H), 7.06(m, 2H), 7.23 (d, 1H, J=7.8 Hz), 7.31 (dd, 1H, J=8.4 Hz and J=2.5 Hz),7.38-7.40 (m, 3H), 7.82 (d, 1H, J=2.1 Hz), 11.3 (br s, 1H); MS (ESI−)m/z 290 ([M+2-H]⁺, 34), 288 ([M−H]⁺, 100. Anal. Calcd. for C₁₄H₁₂ClN₃O₂:C, 58.03; H, 4.18; N, 14.50. Found: C, 57.86; H, 4.30; N, 14.32.

Example 42 Preparation of Compound 42

A round-bottomed flask charged with Compound 5 (0.749 g, 0.00353 mol) intetrahydrofuran (15 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 8.0 mL., 0.00800mol) was added dropwise to the mixture, which was then stirred at −78°C. for 0.5 hours. 1,3-dibromopropane (3.98 g, 0.0198 mol) was addeddropwise. The mixture was allowed to slowly warm to room temperature andstirred overnight. The mixture was then cooled to 0° C. and treated withsaturated aqueous ammonium chloride solution (10 mL). The mixture wasextracted with dichloromethane. The extract was then washed with waterand dried over magnesium sulfate. The solution was concentrated in vacuoto a dark orange oil. The oil was purified by column chromatographyusing first 80% ethyl acetate/hexanes, followed by 5%methanol/dichloromethane as eluents. Fractions containing the desiredproduct were collected and concentrated in vacuo to yield 0.186 g (21%)of Compound 42,2-chloro-5-[(2Z)-2-(nitromethylene)piperidin-3-yl]pyridine, as a yellowsolid. m.p. 132.5-134° C.

Example 43 Preparation of Compound 43

A round-bottomed flask charged with Compound 40 (0.179 g, 0.00070 mol)was treated with methylamine (2.0 M in tetrahydrofuran, 2.0 mL, 0.00400mol). The flask was capped, and the mixture was stirred at 50° C.overnight. The mixture was cooled to room temperature (about 22° C.) andconcentrated in vacuo to afford an orange oil, which was purified bycolumn chromatography using 80% ethyl acetate/hexanes as eluents.Fractions containing the desired compound were combined and concentratedin vacuo to yield 0.117 g (62%) of Compound 43,N-{(Z)-1[1-(6-chloropyridin-3-yl)butyl]-2-nitrovinyl}-N-methylamine, asa pale yellow oil.

Example 44 Preparation of Compound 44

A round-bottomed flask charged with Compound 5 (0.750 g, 0.00354 mol) intetrahydrofuran (15 mL) was cooled to −78° C. Lithiumbis-(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 8.0 mL., 0.00800mol) was added dropwise to the mixture, which was then stirred at −78°C. for 0.5 hours. 1,2-Dibromoethane (3.99 g, 0.0212 mol) was addeddropwise. The mixture was allowed to slowly warm to room temperature andstirred overnight. The mixture was then cooled to 0° C. and treated withsaturated aqueous ammonium chloride solution (17 mL). The mixture wasextracted with dichloromethane. The extract was then washed with waterand dried over magnesium sulfate. The solution was concentrated in vacuoto a dark brown oil. The oil was purified by column chromatography using25% ethyl acetate/hexanes as eluents. Fractions containing the desiredproduct were collected and concentrated in vacuo to yield 0.025 g (3%)of Compound 44,(Z)-1-[1-(6-chloropyridin-3-yl)cyclopropyl]-2-nitroethylenamine, as alight orange solid.

Example 45 Preparation of Compound 45

To a mixture cooled in dry ice/acetone of 234 mg (0.81 mmol) of Compound41 in 2 mL of tetrahydrofuran was added dropwise via syringe 1.78 mL(1.78 mmol) of a 1.0M solution of lithium bis(trimethylsilyl)amide intetrahydrofuran. After stirring for one hour, 0.275 mL (4.4 mmol) ofmethyl iodide was added and the contents were allowed to warm to roomtemperature (about 22° C.) overnight. The solution was then chilled inice and was treated with 5 mL of saturated ammonium chloride and themixture was then extracted with ethyl ether/ethyl acetate. The layerswere separated, the organic phase was washed with brine and was dried(magnesium sulfate). Concentration gave 360 mg of a residue which waschromatographed on silica gel using gradient elution fromdichloromethane to 10% ethyl acetate to give 65 mg (26%) of Compound 45,N-{(Z)-1-[1-(6-chloro-3-pyridinyl)ethyl]-2-nitroethenyl}aniline, as asolid, mp 93-95° C.; ¹H NMR δ 1.46 (d, 3H, J=7.4 Hz), 4.04 (q, 1H, J=7.3Hz), 6.74 (s, 1H), 7.02 (m, 2H), 7.25 (d, 1H, J=7.6 Hz), 7.36-7.40 (m,4H), 7.83 (d, 1H. J=2.3 Hz), 11.5 (br s, 1H); MS (ESI−) m/z 304([M+2-H]⁺, 29), 302 ([M−H]⁺, 83), 255 (100). Anal. Calcd. forC₁₅H₁₄ClN₃O₂: C, 59.31; H, 4.64; N, 13.83. Found: C, 59.23; H, 4.57; N,13.62.

Example 46 Preparation of Compound 46

A mixture of 600 mg (2.81 mmol) of Compound 5, 358 mg (2.81 mmol) of3-chloroaniline, and 653 mg (2.81 mmol) of camphor sulfonic acid in 8 mLof 1,2-dichloroethane was stirred for 4 days at room temperature (about22° C.), was diluted with dichloromethane, and was washed twice withsaturated sodium bicarbonate and was dried (magnesium sulfate).Concentration gave 750 mg of a solid which was recrystallized from ethylacetate to afford 225 mg (25%) of Compound 46,3-chloro-N-{(Z)-1-[(6-chloro-3-pyridinyl)methyl]-2-nitroethenyl}aniline,as a yellow solid, mp 133-134° C.; ¹H NMR δ 3.58 (s, 2H), 6.59 (s, 1H),6.94 (m, 1H), 7.10 (m, 1H), 7.26 (d, 1H, J=8.0 Hz), 7.29-7.37 (m, 3H),7.90 (d, 1H, J=1.8 Hz), 11.2 (br s, 1H); MS (ESI+) m/z 328 ([M+4+H]⁺,10), 326 ([M+2+H]⁺, 73), 324 ([M+H]⁺, 100). Anal. Calcd. forC₁₄H₁₁Cl₂N₃O₂: C, 51.87; H, 3.42; N, 12.96. Found: C, 51.74; H, 3.51; N,12.86. The mother liquor was concentrated to an oil which waschromatographed on silica gel using 7/3 hexanes/ethyl acetate as eluentto give an additional 150 mg (16%) of Compound 46.

Example 47 Preparation of Compound 47

To a mixture cooled in dry ice/acetone of 320 mg (0.987 mmol) ofCompound 46 in 2.5 mL of tetrahydrofuran was added dropwise via syringe2.0 mL (2.0 mmol) of a 1.0M solution of lithium hexamethyldisilazide intetrahydrofuran. The contents were stirred for 1.5 hours and were thentreated with 0.3 mL (4.8 mmol) of methyl iodide and were allowed togradually warm to room temperature (about 22° C.) and stir overnight.The mixture was added to 40 mL of ice water, the pH was adjusted to 6-7with 2.0N hydrochloric acid, and was then extracted twice with ethylacetate. The combined extracts were dried (magnesium sulfate) andconcentrated to give 400 mg of a residue which was chromatographed onsilica gel using gradient elution from dichloromethane to 5% ethylacetate to afford 115 mg (34%) of Compound 47,3-chloro-N-{(Z)-1-[1-(6-chloro-3-pyridinyl)ethyl]-2-nitroethenyl}aniline,as a pale yellow solid, mp 132.5-133.5° C.; ¹H NMR δ 1.47 (d, 3H, J=7.0Hz), 4.00 (q, 1H, J=7.3 Hz), 6.75 (s, 1H), 6.88 (m, 1H), 7.04 (m, 1H),7.28-7.39 (m, 4H), 7.88 (d, 1H, J=2.6 Hz), 11.3 (br s, 1H); MS (ESI+)m/z 342 ([M+4+H]⁺, 6), 340 ([M+2+H]⁺, 59), 338 ([M+H]⁺, 100). Anal.Calcd. for C₁₅H₁₃Cl₂N₃O₂: C, 53.27; H, 3.87; N, 12.42. Found: C, 53.24;H, 4.00; N, 12.32

Example 48 Preparation of Compound 48

A round-bottomed flask charged with Compound 5 (0.498 g, 0.00235 mol) intetrahydrofuran (10 mL) was treated with N,N-dimethylethylenediamine(0.229 g, 0.00260 mol). The flask was put under nitrogen, and themixture was stirred at room temperature (about 22° C.) overnight. Twoadditional equivalents (0.414 g, 0.00470 mol) ofN,N-dimethylethylenediamine was added, and the mixture was stirred foran additional 60 hours. The mixture was concentrated in vacuo to yield0.674 g (97%) of Compound 48,N′-{(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}-N,N-dimethylethane-1,2-diamine,as a yellow solid.

Example 49 Preparation of Compound 49

A round-bottomed flask charged with Compound 42 (0.322 g, 0.00127 mol)in chloroform (20 mL) was treated with N-bromosucciniamide (0.265 g,0.00149 mol) and stirred at room temperature (about 22° C.) for 4.5hours. The mixture was concentrated in vacuo to afford a dark amber oil.The oil was purified by column chromatography using 20% ethylacetate/dichloromethane as eluents. Fractions containing the desiredproduct were collected and concentrated in vacuo to yield 0.140 g (33%)of Compound 49,5-[(29)-3-bromo-2-(nitromethylene)piperidin-3-yl]-2-chloropyridine, as ayellow oil.

Example 50 Preparation of Compound 50

A solution of 1.07 g (5.01 mmol) of Compound 5 and 890 mg (5.00 mmol) ofN-bromosuccinimide in 25 mL of chloroform was stirred at roomtemperature (about 22° C.) for 3 hours and was filtered to afford 1.4 g(96%) of Compound 50,(1E)-1-bromo-3-(6-chloro-3-pyridinyl)-1-nitro-1-propen-2-amine, as ayellow solid, mp 112° C. (dec).

Example 51 Preparation of Compound 51

A round-bottomed flask charged with Compound 5 (0.500 g, 0.00236 mol) intetrahydrofuran (10 mL) was treated with glycine tert-butyl ester (0.310g, 0.00236 mol). The mixture was stirred at room temperature (about 22°C.) overnight. An additional equivalent (0.310 g, 0.00236 mol) ofglycine tert-butyl ester was added, and the mixture was stirred at 40°C. overnight, then heated at 50° C. for an additional 24 hours. Themixture was concentrated in vacuo to afford an orange solid, which waspurified by column chromatography using first 5%methanol/dichloromethane, followed by 20% ethyl acetate/dichloromethaneas eluents. Fractions containing the desired product were combined andconcentrated in vacuo. The residue was dissolved in dichloromethane andwashed with 1.5 equivalents of 1.0 N HCl and dried over magnesiumsulfate. The solution was concentrated in vacuo and recrystallized fromhot ethyl acetate/hexanes to yield 0.040 g (5%) of Compound 51,tert-butyl({(Z)-1-[(6-chloropyridin-3-yl)methyl]-2-nitrovinyl}amino)acetate, as ayellow solid. m.p. 146-147° C.

Example 52 Preparation of Compound 52

To a mixture cooled in an ice-salt bath of 146 mg (0.641 mmol) ofPreparatory Compound W in 1 mL of tetrahydrofuran was added dropwise viasyringe 0.63 mL (0.63 mmol) of a 1.0M solution of potassium t-butoxidein t-butanol. After 0.5 h approximately 40 μL (0.64 mmol) of methyliodide was added and the mixture was allowed to warm to room temperatureand stir for 18 h. The mixture was filtered and the filtrate wasconcentrated to an oil which was identified as the S-methylthioimidateof Preparatory Compound W (¹HNMR: 2.44 ppm 3H-singlet, MS: 242, M+H ion,electrospray positive mode). This oil was then treated with a solutionof 100 mg (2.38 mmol) of cyanamide in absolute ethanol and the mixturewas stirred for 18 h at room temperature. The mixture was concentratedand the residue was partitioned between dichloromethane and 10% aqueouspotassium carbonate. The layers were separated, the aqueous phase wasextracted once with dichloromethane and the combined organics were driedover potassium carbonate. Concentration gave 100 mg of an oil which waschromatographed on silica gel (230-400 mesh) using 9/1dichloromethane/methanol containing 5% ammonium hydroxide to afford 9 mg(6%) of Compound 523-(6-chloro-3-pyridinyl)-2-piperazinylidenecyanamide;¹HNMR (CDCl₃) δ 8.43 (d, 1H, J=2.6 Hz), 7.93 (br s, 1H), 7.70 (dd, 1H,J=8.2 Hz, and J=2.3 Hz), 7.34 (d, 1H, J=7.9 Hz), 4.71 (br s, 1H),3.55-3.69 (m, 1H), 3.47-3.54 (m, 1H), 3.10-3.30 (m, 2H), 2.02 (br s,1H); MS (ES+) m/z 236 ([M+H]⁺); IR (neat) ν cm⁻¹ 2193 (CN).

Biological Testing of Compounds 1-51

Compounds 1-51 were tested in the following tests.

Control of Cotton Aphid (Aphis gossypii) Plant Preparation andInfestation

Hybrid squash plants (Cucurbita pepo cv. Pic-N-Pic) are grown undergreenhouse conditions to seedling stage in 3-inch pots containing MetroMix™. When plants have reached the expanded cotyledons stage, they arepruned to a single cotyledon. All stages of cotton aphids aretransferred to the seedlings by placing infested leaf sections on top ofeach seedling cotyledon 16-24 hours prior to the application of the testmaterial. As the infested sections dry out, the aphids move to thesucculent plant material. The dried leaf sections are removed and plantsare examined to verify adequate infestation prior to application ofexperimental compounds.

Spray Solution Preparation and Application

A single stock solution of technical material for each experimentalcompound is prepared by dissolving each material in 1 milliliter of90:10 acetone:ethanol. One milliliter of this stock solution is thendiluted in 19 milliliters water containing 0.05% of the surfactant Tween20 to form a 50-ppm spray solution. A ten-fold dilution spray solutionis then prepared by transferring 2 milliliters of the 50 ppm solutioninto 18 milliliters of water containing 0.05% of the surfactant Tween20, to form a 5 ppm spray solution.

Application is made with a hand-held DeVilbiss™, airbrush sprayer. Thesquash cotyledons are sprayed on both the upper and lower surfaces ofthe cotyledon until runoff and then all the plants within the treatmentare sprayed evenly until the remaining spray solution is completelyused. Each rate has 4 reps (plants). Controls consist of 8 plantstreated with diluent prepared with a blank stock solution only.

Holding and Grading

Test plants are held for 72 hours at approximately 74° F. and 40%relative humidity with a 24-hour photoperiod, prior to grading. Theeffectiveness of the applications is assessed 3 days after applicationby counting the live aphids (all non-winged stages) on the underside ofeach cotyledon using a dissecting binocular microscope. Live countresults are used to calculate a percent control based on comparison ofthe aphid population results from the experimental treatments comparedto the aphid population on the controls.

Control of Green Peach Aphid (Myzus persicae) Plant Preparation andInfestation

Head cabbage (Brassica oleracea cv. Early Jersey Wakefield) is grownunder greenhouse conditions to seedling stage in 3-inch pots containingMetro Mix™. When plants reach the 2-4 true leaf stage (approximately 12days old), they are infested with all stages of Green peach aphid Myzuspersicae. Infestation occurs 4 days prior to the application of the testmaterials. During the infestation interval, aphids move to the succulentplant material and settle to feed, predominantly on the underside of theleaves. The plants are examined to verify adequate infestation prior toapplication of experimental compounds.

Spray Solution Preparation and Application

A single stock solution of technical material for each experimentalcompound prepared, as above, by dissolving each material in 1 milliliterof 90:10 acetone:ethanol is used to prepare spray solutions for thisbioassay. One milliliter of the prepared stock solution is diluted in 19milliliters of tap water containing 0.05% of the surfactant Tween 20 toform a 50-ppm spray solution.

Application to the infested plants is made with a hand-held DeVilbiss™,airbrush sprayer. The infested cabbage seedlings are sprayed on both theupper and lower surfaces of the leaves until runoff and then all plantswithin the treatment are sprayed evenly until the remaining spraysolution is completely used. Each treatment consists of 4 replicates(plants). The control treatments consist of 8 replicates treated withdiluent prepared with a blank stock solution only.

Holding and Grading

Test plants are held 72 hours at approximately 23° C., 40% relativehumidity and 24 hour photo period prior to grading. The effectiveness ofthe applications is assessed 3 days after application by counting thelive aphids (all non-winged stages) on the underside of each leaf usinga dissecting binocular microscope. Live count results are used tocalculate a percent control based on comparison of the aphid populationresults from the experimental treatments compared to the aphidpopulation on the controls.

Control of Sweetpotato Whitefly (Bemisia tabaci)

Four mg of each test compound are dissolved by adding 4 mL of a 90:10acetone:ethanol solvent mixture to the vial containing the samplecompound. This solution is added to 16 mL of water containing 0.05%Tween 20 surfactant to produce 20 mL of a 200 ppm spray solution.

Five-week-old cotton plants reared in a greenhouse are stripped of allfoliage except for the two uppermost true leaves that were greater than5 cm in diameter. These plants are then placed into a laboratory colonyof whiteflies for two days, exposing the leaves to oviposition by colonyfemales. Adult whiteflies are then removed from the test plants withpressurized air. The spray solution is then applied to the test plantswith a hand-held syringe fitted with a hollow cone nozzle. One mL ofspray solution is applied to each leaf surface (upper and lower) for atotal of 4 mL per plant. Plants are air dried and then placed in aholding chamber (30° C. and 60% relative humidity).

At 12-13 days after application, compound efficacy is evaluated bycounting the number of large nymphs (3^(rd)-4^(th) instars) on each leafusing an illuminated magnifying lens. Percent control is based onreduction of mean number of large nymphs per leaf of treated plantsrelative to that observed in the solvent check (no test compound).

Control of Nilaparvata lugens (Brown Planthopper) and Nephotettixcincticeps (Green Leafhopper) by Foliar Spray Assay Experimentalprocedure

A stock solution of 10,000 ppm is prepared by dissolving 10 mg oftechnical material in 1 mL. Within a 10-mL volumetric flask, a 200 ppmsolution is made by adding 1.05 mL of acetone to 0.2 mL of 10,000 ppmstock; water (8.93 mL) is then added to the level. Within a 5-mLvolumetric flask, a 50 ppm solution is made by adding 0.47 mL of acetoneto 1.25 mL of the previously-made 200 ppm solution; water (4.39 mL) isthen added to the level.

Each replicate of the test area is prepared as follows. Three to fivefour-week old rice seedlings, placed in water in glass cylinders (lowerend closed, upper end open) of 3 cm diameter and height of 5 cm. Withineach cylinder, roots of seedlings are submerged in the water, with theplants being suspended and held by a circular piece of metal screenwrapped around the stems of the seedlings. Another glass cylinder (bothends open) of 3 cm diameter and height of 18 cm is placed on top of thefirst cylinder, and affixed to it with cellophane tape.

After preparation of the test area, application of the compounds ismade. A finely-atomized volume of 0.5 mL of test solution is applied tothe seedlings and the interior of the upper glass cylinder using aventuri-type sprayer driven by compressed air. Plants are then allowedto air dry for a minimum of 3 hr.

After spray residue has dried, test arenas are infested. Fivelaboratory-reared 3^(rd) instar nymphs of either brown planthopper orgreen leafhopper are introduced Into the upper cylinder. A capcontaining a screen is then placed over the top of the upper cylinder.

The cylinders (four replicates per treatment) are held in a growthchamber at 28° C. and 75% relative humidity, with a photoperiod of 14hours. Mortality is observed 6 days after infestation of insects intothe test arena.

Control of Nilaparvata lugens (Brown Planthopper) and Nephotettixcincticeps (Green Leafhopper) by root systemic assay Experimentalprocedure

A stock solution of 10,000 ppm is prepared by dissolving 10 mg oftechnical material in 1 mL. Within a 100-mL volumetric flask, a 10 ppmsolution is made by adding 3.9 mL of acetone to 0.1 mL of 10,000 ppmstock; water (96 mL) is then added to the level. Within a separate100-mL volumetric flask, a 1 ppm solution is made by adding 3.94 mL ofacetone to 0.5 mL of the previously-made 10 ppm solution; water (96.04mL) is then added to the level.

Twenty-five mL of either 10 or 1 ppm test solution are then added toeach of four glass cylinders (lower end closed, upper end open) of 3 cmdiameter and height of 5 cm. Within each cylinder, roots of three tofive four-week old rice seedlings are submerged in the test solution,the plants being suspended and held by a circular piece of metal screenwrapped around the stems of the seedlings.

Another glass cylinder (both ends open) of 3 cm diameter and height of18 cm is placed on top of the first cylinder, and affixed to it withcellophane tape. Five laboratory-reared 3^(rd) instar nymphs of eitherbrown planthopper or green leafhopper are introduced into the uppercylinder. A cap containing a screen is then placed over the top of theupper cylinder.

The cylinders (four replicates per treatment) are held in a growthchamber at 28° C. and 75% relative humidity, with a photoperiod of 14hours. Mortality is observed 6 days after infestation of insects intothe test arena.

Control of Beet Armyworm (Spodontera exigua), Tobacco Budworm (TBW,Heliothis virescens), and Cabbage Looper (CL, Trichoplusia ni)

Technical synthetic organic entities were formulated at 400 ppm in 2acetone:1 tap water. A 25 ppm solution was then prepared from the 400ppm stock. Cypermethrin was used as a standard for comparison and wasformulated at 6.25 ppm in 2 acetone: 1 water. 250 μL of each rate ofeach compound was pipetted upon the surface of 8 mL of lepidopteran diet(modified Shorey) contained in each of ten one-ounce plastic cups (onecup=1 replication).

A second-instar beet armyworm was placed upon the treated diet in eachcup once the solvent had air-dried. The solutions remaining aftercompleting applications to the one-ounce cups were then used as leaf-dipsolutions for 3.5 cm leaf discs cut from cabbage leaves and cottoncotyledons.

Ten discs of each type of plant were dipped until thoroughly coated intoeach rate of each compound (=10 replications of each treatment). Afterair-drying, the treated leaf discs were placed individually intoone-ounce plastic cups. Each dried, treated cotton cotyledon disc wasinfested with a 2^(nd) instar tobacco budworm larva, and each cabbageleaf disc was infested with a 2^(nd) instar cabbage looper larva.

Cups containing the treated substrates and larvae were capped and thenheld in a growth chamber at 25° C., 50-55% relative humidity, and 14hours light:10 hours dark for 5 days. The number of dead insects of 10per species per treatment was then determined.

In the Table below, the headings have the following meanings.

# T-1 T-2 T-3 T-4 T-5 T-6 T-7 T-8 T-9 T-10 T-11 T-12 T-13 T-14 T-15 T-16T-17 T-18 1 G G P P P P G P P P G P G P P P G P 2 G G G G G P G P G P GP G P P P G G 3 G P P P P P P P P P P P P P P P P P 4 G P P P P P P P PP P P P P P P P P 5 G G P P P P P P P P P P P P P P P P 6 G G P G P P PP P P G P P P P P P P 7 G G P G N N N N N N N N P P P P P P 8 G G P N PP P P P P G P P P P P P P 9 G G P P N N N N N N N N P P P P P P 10 G P PP N N N N N N N N P P P P P P 11 N N N N N N N N N N N N P P P P P P 12G G G P P P P P P P G P P P P P P P 13 G P P P N N N N N N N N P P P P PP 14 G P P G N N N N N N N N P P P P P P 15 G G P G N N N N N N N N P PP P P P 16 G P P G N N N N N N N N P P P P P P 17 P P P P P P P P P P PP P P P P P P 18 P G P P P P P P P P P P P P P P P P 19 G P P P P P P PP P P P P P P P P P 20 G G P P P P P P G P G P P P P P P P 21 G G P P PP P P P P P P P P P P P P 22 G P P P P P P P P P P P P P P P P P 23 G GG P P P P P P P G P P P P P P P 24 G G N N N N N N N N N N P P P P P P25 G G P G P P P P P P P P P P P P P P 26 P P P P P P P P P P P P P P PP P P 27 G P G G P P P P P P P P P P P P P P 28 G G P G P P G P P P G PP P P P P P 29 G P P P N N N N N N N N P P P P P P 30 N N N N N N N N NN N N N N N N N N 31 G P P G P P P P P P P P P P P P P P 32 G G P P P PP P P P P P P P P P P P 33 G P P P P P P P P P P P P P P P P P 34 G P PP G P P P P P P P P P P P P P 35 P P P P P P P P P P P P P P P P P P 36G G P P P P P P P P P P P P P P P P 37 P P P P P P P P P P P P P P P P PP 38 P P P P P P P P P P P P P P P P P P 39 G G P P P P P P P P G P P PP P P P 40 G P P P P P P P P P P P P P P P P P 41 P P P P P P P P P P PP P P P P P P 42 G G G G G P G P P P G P G P P P G P 43 G G P P P P P PP P P P P P P P P P 44 G G G N N N N N N N N N P P P P P P 46 P P P P PP P P P P P P P P P P P P 47 P P P P N N N N N N N N P P P P P P 48 P PP P N N N N N N N N P P P P P P 49 G G G G N N N N N N N N P P P P P P50 G G P P N N N N N N N N P P P P P P 51 P P P P N N N N N N N N P P PP P P # means Compound Number. T-1 means Cotton Aphid Testing at 50 ppm.T-2 means Cotton Aphid Testing at 5 ppm. T-3 means Green Peach AphidTesting at 50 ppm. T-4 means Sweetpotato Whitefly Testing at 200 ppm.T-5 means Brown Planthopper Root Systemic Testing at 10 ppm. T-6 meansBrown Planthopper Root Systemic Testing at 1 ppm. T-7 means BrownPlanthopper Foliar Spray Testing at 200 ppm. T-8 means Brown PlanthopperFoliar Spray Testing at 50 ppm. T-9 means Green Leafhopper Root SystemicTesting at 10 ppm. T-10 means Green Leafhopper Root Systemic Testing at1 ppm. T-11 means Green Leafhopper Foliar Spray Testing at 200 ppm. T-12means Green Leafhopper Foliar Spray Testing at 50 ppm. T-13 meansTobacco Budworm Testing at 400 ppm. T-14 means Tobacco Budworm Testingat 25 ppm. T-15 means Beet Armyworm Testing at 400 ppm. T-16 means BeetArmyworm Testing at 25 ppm. T-17 means Cabbage Looper Testing at 400ppm. T-18 means Cabbage Looper Testing at 25 ppm. G means good controlobserved. P means poor control observed. N means compound was nottested.

1. A compound having the following formula

wherein Q can be any five- or six membered heterocyclic ring, X is N,CR, COR, CSO_(n)R (where n=0, 1, or 2), CN(R)₂, C(C═O)R, C(C═S)R,C(C═NR)R, CP(═O)_(m)(R)₂ (where m=0 or 1), or CP(═S)_(m)(R)₂ (where m=0or 1), wherein each R independently can be (a) a C₁₋₁₀, branched orunbranched, alkyl, alkoxy, alkenyl, alkynyl, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylcarbonyl, alkylcarbonothioyl, alkoxycarbonyl,alkylthiocarbonyl, alkoxycarbonothioyl, alkylthiocarbonothioyl, orHC(═NH)—, (b) a C₃₋₁₀, cycloalkyl, or cycloalkenyl, (c) an aryl,heterocyclyl, aryloxy, heterocyclyloxy, arylthio, heterocyclylthio,arylamino, or heterocyclylamino, or (d) a hydro, hydroxy, mercapto,amino, cyano, formyl, nitro, halo, or aminocarbonyl, Z is CN or NO₂, R¹and R² each independently can be (a) a C₁₋₁₀, branched or unbranched,alkyl, alkoxy, alkenyl, alkynyl, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylcarbonyl, alkylcarbonothioyl, alkoxycarbonyl,alkylthiocarbonyl, alkoxycarbonothioyl, alkylthiocarbonothioyl, orHC(═NH)—, (b) a C₃₋₁₀, cycloalkyl, or cycloalkenyl, (c) an aryl,heterocyclyl, aryloxy, heterocyclyloxy, arylthio, heterocyclylthio,arylamino, or heterocyclylamino, or (d) a hydro, hydroxy, mercapto,amino, cyano, formyl, nitro, halo, or aminocarbonyl, R¹ and R² canoptionally be linked together with either a bond or a chain of 1-4atoms, where such atoms can be carbon, nitrogen, sulfur, phosphorus andoxygen, R³ and R⁴ each independently can be, (a) a C₁₋₁₀, branched orunbranched, alkyl, alkoxy, alkenyl, alkynyl, alkylthio, alkylsulfinyl,alkylsulfonyl, alkylcarbonyl, alkylcarbonothioyl, alkoxycarbonyl,alkylthiocarbonyl, alkoxycarbonothioyl, alkylthiocarbonothioyl, orHC(═NH)—, (b) a C₃₋₁₀, cycloalkyl, or cycloalkenyl, (c) an aryl,heterocyclyl, aryloxy, heterocyclyloxy, arylthio, heterocyclylthio,arylamino, or heterocyclylamino, or (d) a hydro, hydroxy, mercapto,amino, cyano, formyl, nitro, halo, or aminocarbonyl, R² and R³ canoptionally be linked together with a chain of 1-4 atoms, where suchatoms can be carbon, nitrogen, sulfur, phosphorus and oxygen, R³ and R⁴can optionally be linked together with a chain of 1-4 atoms, where suchatoms can be carbon, nitrogen, sulfur, phosphorus and oxygen, Eachmember of Q, X, R, R¹, R², R³, and R⁴, which may have a hydrogen atom ina certain position, may instead of having such hydrogen atom, have a,(a) a C₁₋₁₀, branched or unbranched, alkyl, alkoxy, alkenyl, alkynyl,alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl,alkylcarbonothioyl, alkoxycarbonyl, alkylthiocarbonyl,alkoxycarbonothioyl, alkylthiocarbonothioyl, HC(═NH)—,dialkylphosphonyl, or dialkylphosphatyl, (b) a C₃₋₁₀, cycloalkyl, orcycloalkenyl, (c) an aryl, heterocyclyl, aryloxy, heterocyclyloxy,arylthio, heterocyclylthio, arylamino, or heterocyclylamino, or (d) ahydro, hydroxy, mercapto, amino, cyano, formyl, nitro, halo, oraminocarbonyl, in such position.
 2. A composition comprising a compoundaccording to claim 1 and a phytologically-acceptable inert carrier.